Kikuchi’s Disease

Definition

Kikuchi’s disease, or Kikuchi-Fujimoto disease (KFD) is an enigmatic, benign and self-limited syndrome characterized by regional lymphadenopathy with tenderness, predominantly in the cervical region, usually accompanied by mild fever and night sweats.

Initially described in Japan, KFD was first reported in 1972 almost simultaneously by Kikuchi [1] and by Fujimoto et al. [2] as a lymphadenitis with focal proliferation of reticular cells accompanied by numerous histiocytes and extensive nuclear debris [3].

Etiology and pathogenesis

There is much speculation about the etiology of KFD. A viral or autoimmune cause has been suggested. The role of Epstein-Barr virus, as well as other viruses (HHV6, HHV8, parvovirus B19) in the pathogenesis of KFD remains controversial and not convincingly demonstrated [4]. A viral infection is, nonetheless, possible by virtue of clinical manifestations, as described by Unger et al. [6] that include upper respiratory prodrome, atypical lymphocytosis and lack of response to antibiotic therapy, and certain histopathologic features (i.e., T-cells as revealed by immunological marker studies). KFD has also been recorded in HIV- and HTLV-1-positive patients [7].

Some authors hypothesized that KFD may reflect a self-limited autoimmune condition induced by virus-infected transformed lymphocytes [8]. It is possible that KFD may represent an exuberant T-cell mediated immune response in a genetically susceptible individual to a variety of non-specific stimuli [4].

Clinical manifestations

The onset of KFD is acute or subacute, evolving over a period of two to three weeks. Cervical lymphadenopathy is almost always present consisting of tender lymph nodes that involve mainly the posterior cervical triangle. Lymph node size has been found to range from 0.5 to 4 cm, but it may reach 5 to 6 cm and rarely larger than 6 cm. Generalized lymphadenopathy can occur [5,10] but is very rare. In addition to lymphadenopathy, 30 to 50% of patients with KFD may have fever, usually of low-grade, associated with upper respiratory symptoms. Less frequent symptoms include weight loss, nausea, vomiting, sore throat and night sweats [11,12]. Leukopenia can be found in up to 50% of the cases. Atypical lymphocytes in the peripheral blood have also been observed. Involvement of extranodal sites in KFD is uncommon but skin, eye and bone marrow affection, and liver dysfunction have been reported [4]. KFD has also been reported as a cause of prolonged fever of unknown origin [13]. There are occasional reports describing cases of extranodal skin involvement or, even more rarely, of fatal multicentric disease.

Diagnosis

Kikuchi-Fujimoto disease is generally diagnosed on the basis of an excisional biopsy of affected lymph nodes. No specific diagnostic laboratory tests are available. The results of a wide range of laboratory studies are usually normal. Nevertheless, some patients have anemia, slight elevation of the erythrocyte sedimentation rate and even leukopenia. Of note, one third of patients present atypical peripheral blood lymphocytes [5]. Characteristic histopathologic findings of KFD include irregular paracortical areas of coagulative necrosis with abundant karyorrhectic debris, which can distort the nodal architecture, and large number of different types of histiocytes at the margin of the necrotic areas.

Differential diagnosis

The histological differential diagnosis of KFD mainly includes reactive lesions as lymphadenitis associated with SLE or herpes simplex, non-Hodgkin’s lymphoma, plasmacytoid T-cell leukemia, Kawasaki’s disease, myeloid tumor and even metastasic adenocarcinoma [4].

Clinical course and management

Kikuchi-Fujimoto disease is typically self-limited within one to four months. A low but possible recurrence rate of 3 to 4% has been reported [3]. In some few patients, SLE may occur some years later. No risk to other family members is felt to be associated with KFD [7]. Symptomatic measures aimed to relief the distressing local and systemic complains should be employed.

Analgesics-antipyretics and nonsteroidal anti-inflammatory drugs may be used to alleviate lymph node tenderness and fever. The use of corticosteroids has been recommended in severe extranodal or generalized KFD but is of uncertain efficacy. Surgical consultation may be indicated for a diagnostic excisional lymph node biopsy. Patients with KFD require a systematic survey and regular follow-up for several years to rule out the development of SLE. The cervical lymphadenopathy runs a benign course and appears to resolve spontaneously 1 to 6 months after definite diagnosis.

 

Adapted from Orphanet Journal of Rare Diseases 2006, 1:18  doi:10.1186/1750-1172-1-18

Answer to CC #5

Tough case this week! Case Challenge #5 presented a 28 yo female with fever, cervical LAD, and atypical lymphs.  Biopsy revealed necrotizing lymphadenitis with histiocytes, nuclear debris, and negative organism stains.

 Which is the most likely diagnosis?

KikuchiResults
The correct answer is:

Kikuchi’s Disease

  • Benign disease of young (women) with acute fevers and unilateral cervical LAD (esp posterior)
  • Associated with uveitis, aseptic meningitis, HSM, rash and arthritis
  • Often leukopenic with atypical lymphs
  • Dx by biopsy showing preserved architecture, necrotizing histiocytic infiltrate with phagocytosed nuclear debris

Great job! Look forward to a easier case challenge next week 🙂

The Incidental Thyroid Nodule

Dr. Saad Khan, from the UTSW division of Hematology/Oncology, presented an update on the diagnosis and treatment of thyroid cancer. A point important for general internists is the evaluation of incidentally discovered thyroid nodules. The algorithm below may help clarify the diagnostic process:

 

 

 

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“That Alkaline Phosphatase Seems Really High…”

Today at Morning Report we talked about how to approach a patient with an elevated alkaline phosphatase. There’s a fantastic review article from Clinical Liver Disease by Dr. Siddique and Dr. Kowdley from Virginia Mason Medical Center about how to evaluate and work up a patient who presents with an abnormally high alkaline phosphatase. Key points, tables, charts below from the article:

  • Highest concentration of AP is in liver and bone. But also found in intestine, kidney, and placenta.
  • It can vary with age, gender, and blood type.
  • Try to find the source of the elevated AP – fractionation of isoenzymes by electrophoresis or obtaining 5’nucleotidase and gamma glutamyl transpeptidase (GGT) levels, both of which are elevated in hepatobiliary disease
  • Determine whether cholestasis is secondary to intrahepatic or extrahepatic disease process keeping in mind some diseases can cause both such as primary sclerosing cholangitis

Figure 1. Algorithm in evaluating elevated AP

Table

Figure 2. Categories based on liver tests

Table2

Check out the full article below by clicking the link:

Approach to the Patient with Elevated Alkaline Phosphatase 

(Figure 1 and 2 from Siddique, Kowdley. Clin Liver Dis. 2012.)

A New Approach in Reducing Risk of Peanut Allergy? Promising Study Released!

This week’s NEJM released a study (LEAP Trial) from King’s College in London looking at reducing the risk of developing peanut allergies in infants by having them consume peanuts. The authors observed decreased frequency of peanut allergies in the group that consumed peanuts versus the group that avoided. Dr. Rebecca Gruchalla, Professor and Director of the UT Southwestern Allergy and Immunology Division, co-wrote an editorial in the NEJM describing the trial and its potential effect on future studies and management of food-based allergies. Check out the original study and Dr. Gruchalla’s editorial below!

Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy

Preventing Peanut Allergy through Early Consumption – Ready for Prime Time? 

Rewarming in Accidental Hypothermia

REWARMING METHODS

Passive:

  1. Remove clothing
  2. Dry patient
  3. Cover with blankets / space blanket
  4. Provide warm sugary drinks

Active External:

  1. Forced Air Rewarmer (eg: Bair Hugger) ‐ to trunk only to reduce core temperature afterdrop.
  2. Arctic Sun (for moderate / severe).

Active Internal:

  1. Warmed fluids (D5 NS @ 40-42 C) – Initially 250-500mL bolus, repeat based on clinical
  2. Warm, humidified oxygen. By facemask or consider CPAP – by ETT if intubated.
  3. Peritoneal Lavage – 2 liters of diasylate @ 40 – 45 C, remove after 20-30 minutes. Rewarming rate of 1-3 C / hr.
  4. Body cavity lavage – Through Foley or NGT / OGT. 500mL boluses or continuous Consider risk of fluid / electrolyte shifts.
  5. Closed Thoracic Lavage – 2 large bore (38-40 fr) chest tubes in each hemithorax (one at mid clavicular line @ 2nd / 3rd interspace, second at post. axillary line @ 5th / 6th interspace). Infuse warmed (40-42 C) saline and drain though posterior tube.
  6. Thoracotomy with Mediastinal Lavage – 1-2 liters of warmed NS to mediastinum, remove after 1-2 minutes. May utilize cardiac massage and internal defibrillation. Highly Invasive, requires disposition to OR.

Extracorporeal:

  1. Continuous Venovenous Rewarming (CVVR) – 2-3 C / hr.
  2. Continuous Arteriovenous Rewarming (CAVR) – 3-4 C / hr. Requires adequate MAP. Can be performed in ED with proper equipment.
  3. Hemodialysis – 3-4 C / hr. Requires adequate MAP. Possible to correct electrolyte and toxic abnormalities. Requires dialysis staff.
  4. Cardiopulmonary Bypass – Most rapid rewarming (8-10 C / hr). Provides full cardiopulmonary support for hemodynamically unstable patients.

Created by Jack Gervais MD, Matt Sholl, MD, and Jeff Holmes MD at Maine Medical Center

Internal Medicine Journal Watch – February 2015

STRAIGHT FROM THE HOUSESTAFF – the February 2015 Internal Medicine Journal Watch! They have summarized important issues in clinical practice, from Metformin in CKD to pre-exposure prophylaxis for HIV. There is even an EKG challenge at the end, if you are up for it! You will have to view this post on our website to access the PDF.  There is a quick run down of the topics below:

Endocrinology

  • American Diabetes Association’s Standards of Medical Care in Diabetes – 2015.
    • Dr. Jeremy Warshauer reviewing Grant RW, et al. Diabetes Care 2015 Jan;38 Supplement 1
  • Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review
    • Dr. Nicolas Barros reviewing Inzucchi, SE, et al. JAMA 2014; 312(24):2668-2675

Rheumatology

  • Preliminary analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis
    • Dr. Brian Skaug reviewing Minier T, et al. Ann Rheum Dis 2014;73: 2087–2093

Healthcare Policy

  • Using drugs to discriminate – adverse selection in the insurance marketplace
    • Dr. Ashish Gupta reviewing Jacobs DB and Sommers BD. N Engl J Med. 2015 Jan 29;372(5):399-402

General Internal Medicine

  • Disorders of Plasma Sodium — Causes, Consequences, and Correction
    • Dr. Nicolas Barros reviewing Sterns, R, et al. NEJM 2015; 372:55-65
  • Acid–Base Problems in Diabetic Ketoacidosis
    • Dr. Nicolas Barros reviewing Kamel K, et al. NEJM 2015 ; 372:546-554

Platelet Transfusion

  • A Clinical Practice Guideline From the AABB
    • Dr. Nicolas Barros reviewing Kaufman RN, et al. Ann Intern Med. 2015 Feb 3;162(3):205-13

Nephrology

  • Association of Albumin-Creatinine Ratio and Cystatin C With Change in Ankle-Brachial Index: The Multi-Ethnic Study of Atherosclerosis (MESA)
    • Dr. Ben Jenny reviewing Garimella P, et al. Am J Kidney Dis. 2015;65(1):33-40

Infectious Disease

  • Tenofovir-Based Preexposure Prophylaxis for HIV Infection Among African Women
    • Dr. Brad Cutrell and Dr. Nicolas Barros reviewing Marrazzo J, et al. 2015; 372:509-518
  • Infectious Diseases Diagnosis and Treatment of C. difficile in Adults: Systematic Review
    • Dr. Brad Cutrell and Dr. Nicolas Barros reviewing Bagdasarian N, et al. JAMA 2015; 313(4):398-408

Hepatology

  • An interferon-free antiviral regimen for HCV after liver transplantation
    • Dr. Jan Petrasek reviewing Kwo et al., NEJM. 2014; Dec 18;371(25):2375-82
  • Decreasing Mortality Among Patients Hospitalized with Cirrhosis in the United States From 2002 through 2010
    • Dr. Jan Petrasek reviewing Schmidt et al., Gastroenterology. 2015 Jan 23.

Cardiology

  • Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents (DAPT trial)
    • Dr. Ben Jenny reviewing Mauri L, et al. N Engl J Med. 2014 Dec 4;371(23):2155-66.

EKG Challenge

  • Dr. Ben Jenny
  • Untitled
All of the work above comes from the IMJW Editorial Board (with Dr. Brad Cuttrell): Jan Petrasek, Purav Mody, Nicolas Barros, Ragisha Gopalakrishnan, Jeremy Warshauer, Shetal Patel,  Ben Jenny (not Jennings), Vishwanatha Lanka, Brian Skaug, Ashish Gupta, and Roma Mehta!

Advice for Physicians in Training: 40 Tips From 40 Docs

On Professional Relationships

 

 

Helping patients and families deal with death is one of the most rewarding aspects of practicing medicine. Becoming comfortable talking about death, however, is not easy, and physicians who are good at it didn’t get that way overnight. When you find one who is, observe and emulate them.

David Juurlink, Advice for Physicians in Training: 40 Tips From 40 Docs,The Winnower2:e142006.67645 (2014). DOI:10.15200/winn.142006.67645

Myxedema Madness

Introduction

The term “Hashimoto encephalopathy” (HE) was used perhaps for the first time in 1991 by Shaw (1), who collected five cases with similar symptoms such as seizures, disorientation, frequent episodes of alternating hemiparesis, high protein levels in the cerebrospinal fluid and electrocardiographic abnormalities. However, these patients also had hypothyroidism and positive thyroid antibodies. However, in 1966, a case was described of a 63-year-old man who had seizures, disorientation, frequent episodes of alternating hemiparesis, high protein levels in the cerebrospinal fluid, electrocardiographic abnormalities and biopsy-confirmed Hashimoto thyroiditis (2) Because several cases were later published that showed a similar outcome but with entirely different clinical presentations, the question has been raised whether HE is a true syndrome. The same authors concluded that several patients presented with various signs of encephalopathy and high thyroid antibody levels together with the responsiveness to glucocorticoid therapy and that such convergence seems unlikely to result from chance (3). There also appears to be no evidence of any specific pathogenic role for thyroid antibodies in the origin of such encephalopathy, and several authors hypothesized that these antibodies are only markers of a possibly unrelated autoimmune disease affecting the brain. The term HE is now commonly used for the few hundred patients published so far, whereas some other terms such as “myxedema madness” (4), “encephalopathy associated to autoimmune thyroid disease” (5) or “steroid-responsive encephalopathy with antibodies to thyroperoxidase” (SREAT) (6) have been mostly abandoned.

Clinical presentation

HE is a relatively rare condition with a broad range of clinical presentation. Thus, there is a high risk that patients with this serious disease will be misdiagnosed and thus even mistreated, sometimes for a considerably long time. Because the finding of TPOab in blood is one of the most frequent signs accompanying HE, it is generally recommended as a powerful diagnostic tool in all cases of unexplained fluctuating encephalopathy. The most frequently observed signs include epilepsy-like seizures resistant to anticonvulsive treatment, confusion, headaches, hallucinations, stroke-like episodes, coma, impairment of cognitive function, behavioral and mood disturbance, focal neurological deficits, disturbance of consciousness, ataxia, and presenile dementia.
Although the majority of described cases showed neural symptoms for months before the acute onset, in some cases a dramatic acute onset appeared. A review of 30 patients revealed two types of clinical presentation, e.g., that with acute or insidious onset (21). In general, this view seems to be supported by an overview of several patients as summarized below. However, a third type of onset and clinical course of a variety of neurologic complications was recently defined as “relapsing-remitting manner including cognitive deterioration and psychiatric illness” (8).
HE appears in all age groups including children (22), and as much as approximately 70 to 80 percent of the patients are women and girls. It was repeatedly underlined that, especially in children, several cases of such encephalopathy remained unrecognized for a considerable time (8, 23, 24). However, in several cases, a clear thyroid disorder, mostly presenting as hypofunction, could provide useful streamlining diagnostic guidance in patients with various neuropsychiatric signs. Such signs usually continue after the thyroid treatment or even show a worsening that is generally considered to be one of the most important signs of HE, as the specific neuropsychiatric problems usually accompanying each thyroid disorder disappear after treatment with thyroxine.

Diagnosis

Some useful reports have appeared regarding the frequency of individual symptoms and/or laboratory findings in patients with HE. Chong et al. (3) summarized 105 cases and concluded that in most cases, the diagnosis was based on the disturbed consciousness, negative finding of bacterial or viral infection in the cerebrospinal fluid, and high level of thyroid antibodies, with latter found in 100% of the cases, although the antibody level usually did not appear to be correlated with the severity of the illness. Moreover, a high protein level in the cerebrospinal fluid appeared in 78% of cases, abnormal electroencephalography in 98% and various mostly nonspecific abnormalities on magnetic resonance imaging in approximately 50%. Magnetic resonance revealed ischemic areas, multiple tumors, granulomas or various degenerative processes in 60% of the cases, and SPECT examinations showed decreased perfusion in the cortical areas or basal ganglia (25). From 1995 to 2003, 20 patients with Hashimoto encephalopathy were examined (26) and tremor was found in 16, transient aphasia in 16, myoclonus in 13, walking impairments in 13, seizures in 12 and sleeping disorders in 11 of them.

=== CSF Analysis
Cerebrospinal fluid analysis, electroencephalography, and neuroimaging studies do not show consistent findings to support the diagnosis. Physicians’ awareness of this complication is of great importance because most patients respond dramatically to corticosteroid therapy. Moreover, early recognition might also prevent a costly diagnostic work-up in patients with unexplained encephalopathy. In one patient, a follow-up for the IgG level in the CSF was found to be useful; after the IgG was found to be increased, the treatment was repeated with a partial clinical improvement and decline in the CSF level of IgG. Following high-dose steroid treatment, the patients’ clinical condition stabilized and a CSF analysis showed even further IgG decline (27). Thus far, approximately 150 cases have been published, although this disease probably remains under-diagnosed because it is not yet generally known and there were also presumably several additional cases that simply were not published at all. As clearly follows from the literature, an unusually wide variety of symptoms at presentation effectively obscures the basic pathogenetic process of HE. Because thyroid antibodies recently became considered as a useful marker for HE, it is recommended to check for their elevation not only in the blood but also in the CSF, particularly in cases presenting the triad of encephalopathy with EEG slowing and increased protein level in the CSF as well as in all unexplained cases with a variety of nonspecific neuropsychiatric symptoms, generalized or partial seizures, hallucinations, or status epilepticus.

=== MRI
The MRI manifestations of HE can vary from normal appearance, ischemic lesions, demyelination, and vasogenic edema to atrophy. The diverse MRI features of HE reported in the literature make it difficult to understand the pathological process and monitor the prognosis. To investigate the dynamic changes of MRI manifestations in HE, two cases of HE were retrospectively analyzed with a series of longitudinal MRI data. Although similar acute ischemic manifestations were observed at the onset of HE in both cases, at follow-up, we observed different evolutions of HE on MRI between the two cases, which might partially account for the diversity of MRI findings (for example, a certain stage of HE). The clinical and MRI findings at follow-up also indicated that early treatment contributed to the recovery of the lesions (28).

Treatment

Once a firm HE diagnosis is made, corticosteroid treatment usually provides a dramatic recovery, but several adverse outcomes, relapses and temporary or permanent spontaneous remissions have also been reported. At the same time, the high effectiveness of corticoid treatment in nearly all HE patients strongly supports an common autoimmune origin. Even in the absence of diagnostic serological findings, clinical improvement with corticosteroids may be provide the only evidence of autoimmune encephalopathy (29). However, it is always necessary to consider the possible adverse effects of corticosteroid therapy (30). Additionally, a case of HE was described that improved only after intravenous immunoglobulin treatment (31).

 

International Journal of Endocrinology and Metabolism. 2012 December; 10(2): 506-514. , DOI: 10.5812/ijem.4174