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A Headache of a Diagnosis

A Headache of a Diagnosis

The new england journal of medicine

Clinical Problem-Solving

Caren G. Solomon, M.D., M.P.H., Editor A of a Diagnosis

Robert M. Stern, M.D., Marlise R. Luskin, M.D., M.S.C.E., Roger P. Clark, D.O., Amy L. Miller, M.D., Ph.D., and Joseph Loscalzo, M.D., Ph.D.​​

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors’ commentary follows.

A 24-year-old man presented to a university health center in January with a persistent From the Department of Medicine, Brig­ headache that began abruptly 6 days earlier. He noted nonpulsating discomfort in the ham and Women’s Hospital, and Har­ vard Medical School — both in Boston. right retro-orbital area that was not relieved by ibuprofen (400 mg four times daily). Address reprint requests to Dr. Miller at He reported no prodromal symptoms, sensitivity to light or sound, neurologic symp- Brigham and Women’s Hospital, 75 Fran­ toms, , or and had no history of . A day before presenta- cis St., Boston, MA 02115, or at ­almiller@​ ­bwh​.­harvard​.­edu. tion, he noted subjective . The patient was evaluated, and amoxicillin was pre- scribed for presumed acute rhinosinusitis. N Engl J Med 2018;379:475-9. DOI: 10.1056/NEJMcps1803584 Copyright © 2018 Massachusetts Medical Society. In a young, healthy patient, a viral syndrome would appear to be the most likely explanation for this patient’s clinical presentation. This history is not typical for a patient with a primary headache syndrome. Tension headaches are more com- monly bilateral. His headache is not accompanied by the characteristic features of headaches, including aura, a pulsating character, and associated nausea, vomiting, or hypersensitivity to light or sound. Cluster headache, primary headache, and primary stabbing headache all have different presentations. Further- more, the absence of a history of headache and the duration of symptoms argue against a primary headache syndrome. Although many patients receive a diagnosis of and treatment for headaches as- sociated with rhinosinusitis, true sinus headaches are uncommon. Many patients who receive a diagnosis of sinus headache instead have migraine headaches trig- gered by an upper respiratory or accompanied by nasal symptoms due to vasomotor instability. Although can be attributable to , this patient has no other symptoms that suggest sinusitis. Most often, the combination of fever and headache is due to a systemic infectious process, but nonvascular intracranial disor- ders (e.g., central nervous system [CNS] lymphoma) and cervical or cranial vascular disorders (e.g., subarachnoid hemorrhage) can also cause these symptoms. I would favor further evaluation before initiating empiric antibiotic therapy.

The patient’s headache and fever persisted. Two days after presentation, he noted new neck stiffness and . He presented to the emergency department for further evaluation, reporting malaise, subjective , and decreased appetite. He had no upper respiratory symptoms, rash, , or nausea.

The development of neck stiffness suggests the possibility of meningitis. Although the classic presentation in patients with meningitis includes fever, neck stiffness, and altered mental status, fewer than two thirds of patients with meningitis pres- ent with all three symptoms. Given this patient’s subacute course, it is unlikely

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that he has acute purulent meningitis (from in- urine) that has contaminated water or soil. This fection with or condition has two clinical phases: an initial phase pneumoniae), but viral, zoonotic, fungal, or tuber- of fever, rigors, myalgias, and headache and a culous infection is possible. A careful history of severe second phase that can include meningitis, exposures should be obtained. Aseptic meningi- kidney failure, or liver failure. Finally, relapsing tis caused by medications, autoimmune disease, fever is associated with Borrelia turicatae infection, or should also be considered. which is also transmitted by a tick bite and leads to the sudden onset of high fever followed by The patient’s medical history was unremarkable: recurrent febrile episodes with myalgias, , he had no allergies and took no medications regu- and abdominal discomfort. Additional larly. He was a graduate student. He reported no endemic to Texas or the northeastern United recent sexual activity but indicated that he had States, including the , , used condoms with female sexual partners in the , and , are less likely to past. He drank alcohol socially, smoked two ciga- be acquired during the winter months. rettes a month, and smoked marijuana occasion- ally. There was no family history of cancer. He had On physical examination, the temperature was lived in Chicago, Maryland, and Massachusetts. 39.4°C, the heart rate 74 beats per minute, the His only recent travel had been to Texas, where he blood pressure 118/65 mm Hg, the respiratory rate had spent 4 days vacationing on a cattle ranch; his 16 breaths per minute, and the oxygen saturation headache had begun on the last day he spent at the 98% while the patient was breathing ambient air. ranch. He had no recent sick contacts, including He appeared comfortable, with anicteric sclerae, his fellow travelers. moist mucous membranes, and a clear orophar- ynx. The neck was supple, with a full range of The patient’s travel history raises the possibility motion and no . Both lungs were of an exposure to a source endemic to Texas or clear on auscultation. Cardiovascular examination associated with cattle, although processes unre- revealed a regular rate and rhythm with normal lated to his recent trip remain possible. Rocky heart sounds. The abdomen was soft, without hep- Mountain , caused by infection with atomegaly or splenomegaly. The arms and legs rickettsii, which is transmitted by a tick were warm and well perfused, with no edema. bite, occurs throughout the United States and in There were no rashes or skin lesions. The cranial warm states can be transmitted during the winter nerves, motor strength, sensation, and gait were months. Symptoms are generally nonspecific and normal. Neither Kernig’s sign (the inability to include fever, headache, malaise, myalgias, and extend the knee with the hip at 90-degree flexion) rash. Additional sources of rickettsial infection nor Brudzinski’s sign (spontaneous flexion of the found in Texas, including R. typhi (the cause of hip with passive flexion of the neck) was present. murine ), R. prowazekii, and R. parkeri, can result in symptoms similar to those of Rocky The patient has a temperature–pulse dissociation. Mountain spotted fever (although patients with This condition was first described in patients R. parkeri infection often present with an eschar). with yellow fever and is often associated with (caused by ) is spread conditions caused by infection with obligate in- through contact with animal excretions and re- tracellular organisms, including Rocky Mountain sults in a flulike illness that includes high fevers, spotted fever, , Q fever, leptospi- , and headache, but the incubation period rosis, and serotype Typhi. Tem- (approximately 3 weeks) is not consistent with perature–pulse dissociation may also be associ- this patient’s history. , transmitted by ated with CNS lesions, lymphoma, fevers related fluids from livestock, including cattle, can lead to medications, and beta-blockade. The absence to a systemic infection that is associated with of a rash does not rule out a rickettsial infection, fever, , and headache or to a local- since rash is frequently absent on initial presen- ized infection focused in nearly any organ system. tation. The absence of lymphadenopathy, hepato- The disease has an incubation period of 1 to megaly, or splenomegaly argues against lym- 4 weeks, a timeline that is also inconsistent with phoma or Epstein–Barr (EBV) infection. this patient’s history. is spread Both Kernig’s sign and Brudzinski’s sign lack the through exposure to animal urine (including cow sensitivity for the diagnosis of meningitis.

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The white-cell count was 5100 per cubic milli- Fever, headache, and rash constitute the classic meter (67% neutrophils, 17% lymphocytes, 7% triad found in both Rocky Mountain spotted monocytes, and 7% bands), the hemoglobin level fever and murine typhus. In the medical litera- 12.9 g per deciliter, and the platelet count 132,000 ture, the rash in murine typhus is described as per cubic millimeter. The mean corpuscular vol- beginning on the trunk and spreading outward, ume was 86 fl (normal range, 80 to 100). The so- sparing the palms and soles. In contrast, the rash dium level was 134 mmol per liter, and the basic in Rocky Mountain spotted fever is described as metabolic panel was otherwise normal. The level beginning on the wrists or ankles, spreading to of alanine aminotransferase was 95 U per liter the trunk, and including the palms and soles. (normal value, <49), aspartate aminotransferase Although this patient’s rash fits the classic de- 102 U per liter (normal value, <40), alkaline phos- scription of that associated with murine typhus, phatase 66 U per liter (normal range, 27 to 129), in practice, the rashes of both murine typhus and and total bilirubin 0.8 mg per liter (normal range, Rocky Mountain spotted fever are variable, and 0.3 to 1.2). The results of urinalysis were unre- the distribution and evolution of a rash are not markable. reliable means of discriminating between these diagnoses. An elevated monocyte count has been reported When a presumptive diagnosis of either mu- with specific infections, including Rocky Moun- rine typhus or Rocky Mountain spotted fever is tain spotted fever, murine typhus, brucellosis, made, empiric therapy should be and disseminated candidiasis. The mild normo- initiated (in the absence of contraindications) cytic anemia and mild in this while the results of serologic tests are awaited, patient are consistent with an infectious process since its use is associated with a significantly re- leading to bone marrow suppression. The elevated duced duration of febrile illness. If initial sero- aminotransferase levels are a nonspecific finding logic testing is negative, repeat testing should be that can result from a range of infectious and considered, since test results may be negative noninfectious processes. early in the course of infection.

Chest radiography and computed tomography of Doxycycline was prescribed, and serologic tests the head were performed, and the results were for Rocky Mountain spotted fever, murine typhus, unremarkable. The result of an EBV heterophile Lyme disease, ehrlichia, anaplasma, cytomegalo- antibody test was negative. The fever resolved af- virus infection, EBV infection, and herpes simplex ter the administration of acetaminophen, and the virus infection were ordered. Within 72 hours af- patient was discharged home with instructions to ter the patient began to receive doxycycline, the alternate between acetaminophen and ibuprofen fever and headache resolved, and his energy level as needed for fever. and appetite improved. R. typhi IgM titers were greater than 1:64, and IgG titers were 1:512, find- EBV infection would be an unlikely cause of this ings that were consistent with a probable diagno- clinical presentation, but it is not ruled out by the sis of murine typhus (IgM or IgG ≥1:128). All monospot test alone, since the test lacks sensi- other serologic tests, including those for R. rick- tivity early in the course of infection. On the ettsii (IgM <1:64 and IgG <1:64), were negative. basis of the patient’s clinical history, findings on physical examination, and initial laboratory stud- Commentary ies, Rocky Mountain spotted fever and murine typhus are highest on the differential diagnosis, The patient’s symptoms and the results of phys- but we would favor broad serologic testing. Lum- ical examination and laboratory tests were con- bar puncture could be considered to assess for sistent with murine typhus. However, the sug- aseptic meningitis, but it would be reasonable to gestive travel history and additional clinical pursue serologic testing first. features — the time course of symptoms, tem- perature–pulse dissociation,1 mild thrombocyto- Two days later, the patient presented to an infec- penia with transaminitis, and rash — were re- tious disease clinic for further evaluation. Physical quired to prompt consideration of the diagnosis, examination revealed a new, faint pink, morbilli- the laboratory tests ordered, and the treatment. form rash on the trunk, sparing the arms and legs. Murine typhus, also known as endemic typhus

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R. typhi

Rat reservoir (Xenopsylla cheopis) Rat–rat-flea transmission cycle

Humans can be infected with murine typhus through contact (Ctenocephalides felis) with vectors for R. typhi

Cat Opossum or cat–cat-flea reservoir transmission cycle

Opossum R. typhi reservoir

Figure 1. Zoonotic Cycle of . The historical zoonotic cycle of rat reservoir and the rat­flea vector for R. typhi have been largely supplanted in suburban areas of the United States by the opossum or cat reservoir and the cat­flea vector. Humans are “accidental” hosts, in which the parasites cannot complete their life cycle.

and fleaborne typhus, is a typhus-group rickett- reservoir, with serving as a vector to main- siosis caused by R. typhi, a gram-negative, obligate, tain a rat–flea–rat life cycle. Human infection intracellular bacillus. Infection from two addi- results from immediate inoculation with flea tional rickettsial organisms, R. felis and R. prowa- feces at the site of a flea bite. Beginning in 1945, zekii, lead to similar clinical symptoms and sero- an aggressive campaign to eliminate rat and flea logic findings and can be differentiated only populations was initiated. This effort reduced with polymerase-chain-reaction (PCR) testing.2,3 the annual incidence of murine typhus to fewer Murine typhus was prevalent throughout the than 100 cases by the late 1980s.2,4 In 1988, southeastern United States and California dur- murine typhus was removed from the National ing the first half of the 20th century, with an Notifiable Diseases Surveillance System but re- annual incidence exceeding 5000 cases in the mained endemic to southern and central Texas early 1940s.4,5 were the primary animal and southern California. In the past 15 years,

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there has been a substantial increase in the an- and in almost all patients within 15 days after nual incidence of murine typhus in both loca- the onset of illness.2,3 Laboratory diagnosis of tions.6,7 The increased incidence appears to re- murine typhus can also be made on the basis flect a shift in the life cycle of R. typhi from of a positive result on PCR testing, bacterial a rat–flea–rat cycle to an opossum–cat flea– isolation from a clinical specimen, or a positive opossum cycle in both Texas and California finding on IFA. However, these tests either lack Fig. 1.2,5 sensitivity (in the case of PCR testing and bacte- The symptoms and findings in murine typhus rial isolation) or are not generally available (in are generally nonspecific. A systematic review of the case of bacterial isolation and IFA).10,11 studies involving 2074 patients showed that after Treatment for murine typhus should be initi- an incubation period of approximately 5 to 15 ated while awaiting confirmatory test results. days, the most common symptoms were fever Randomized trials are lacking to assess the ef- (in >99% of patients), headache (81%), malaise fectiveness of various antibiotic regimens in pa- (67%), chills (63%), and myalgias (52%), and the tients with murine typhus, but clinical experience most common findings on physical examination supports the use of doxycycline as the first-line were rash (48%), hepatomegaly (22%), conjunc- antibiotic treatment in nonpregnant adults and tivitis (18%), and splenomegaly (17%).8 Common children older than 8 years of age. The use of laboratory findings include elevated levels of the doxycycline is associated with a decrease in the aminotransferases (79%) and lactate dehydroge- average length of febrile illness from approxi- nase (73%), hypoalbuminemia (60%), and throm- mately 2 weeks to less than 4 days2,8; it should bocytopenia (42%).8,9 The classic triad of fever, be continued for 3 days after resolution of symp- headache, and rash is found in approximately toms. Ciprofloxacin is also effective and should one third of patients. In approximately 25% of be used for patients in whom doxycycline is con- patients, more severe complications develop, in- traindicated.11,12 cluding respiratory failure, aseptic meningitis, Murine typhus, long considered to be a rare seizures, acute renal failure, and septic shock,8 disease in the United States, is now increasing but the mortality is less than 5% even without in both frequency and geographic distribution. antibiotic treatment.2 This case highlights the relevance of a careful The standard for diagnosis of murine typhus travel history and the need to consider the pos- is the indirect immunofluorescence assay (IFA). sibility of this infection in patients with relevant A single titer of 1:128 or higher suggests a prob- exposures. able diagnosis, and an increase in the antibody titer by a factor of four or more over 2 to 4 weeks No potential conflict of interest relevant to this article was reported. is diagnostic. Diagnostic IFA titers are present in Disclosure forms provided by the authors are available with 50% of patients 1 week after the onset of illness the full text of this article at NEJM.org.

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