Advertisement
Mayo Clinic Proceedings Home

31-Year-Old Woman With Chronic Daily Headache and Alopecia

      A 31-year-old woman with a history of temporomandibular joint syndrome presented to our internal medicine consultation clinic with daily headache of 7 months' duration. Symptoms began with a 3-week illness of low-grade fever, nonproductive cough, and gradual onset of persistent daily headache with occasional neck pain and stiffness. The headache was described as diffuse, dull and nonthrobbing in nature, scoring 5 on a scale of 1 to 10, but 8 at it’s worst. The headache was aggravated by exertion and improved with rest. One month after onset of the illness, she experienced episodes of blurry vision without photophobia, eye pain, or lacrimation. Ophthalmology evaluation at an outside facility was unrevealing. At 5 months after the illness began, she was treated for presumed sinusitis by local providers with 1 dose of ceftriaxone intramuscular injection and a course of azithromycin, which produced minimal relief of her headaches. Her other symptoms included progressive fatigue, mental fogginess, weight loss of 11 kg, nausea, and paresthesia of the hands and feet without focal weakness. She had been in a monogamous relationship for 4 years that involved unprotected intercourse, but prior to that she was not involved in high-risk sexual activity such as multiple partners. She had no history of tobacco, drug, or alcohol use, sexually transmitted diseases, foreign travel, or tuberculosis exposure. She had no family history of headaches and no personal or family history of thrombophilia, recurrent miscarriages, bleeding disorders, or autoimmune disorders. Findings on magnetic resonance imaging (MRI) of the brain without gadolinium performed elsewhere were considered normal.
      On physical examination at our clinic, her pupils were reactive to light and accommodation, and extraocular movements were intact. Fundoscopic examination revealed flat optic discs with normal vasculature. Her neck was supple with full range of motion and no tenderness. Responses in cranial nerves II through XII were intact. She had full motor strength throughout her body, normal findings on sensory examination, and no skin lesions. The outside brain MRI was reviewed by a neuroradiologist, who reported subtle dural thickening up to 2 mm along both cerebral convexities that was consistent with hypertrophic pachymeningitis.
      • 1.
        Which one of the following is the most likely cause of this patient's chronic daily headache?
        • a.
          Chronic migraine
        • b.
          Hemicrania continua
        • c.
          Idiopathic intracranial hypertension
        • d.
          Carcinomatosis
        • e.
          Chronic meningitis
      Chronic daily headache is defined as headache that occurs more than 15 days per month for a duration of at least 3 months.
      Headache Classification Subcommittee of the International Headache Society
      The International Classification of Headache Disorders. 2nd ed.
      Primary headaches such as migraine, tension-type, and cluster cephalgias may only be diagnosed after secondary causes have been ruled out. Secondary causes include trauma, infection, anatomic defects (eg, Chiari malformation), neoplasms, and high or low cerebrospinal fluid (CSF) pressure among others. A chronic migraine is defined as daily headache with at least two of the following: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by routine physical activity. It also must include at least one of the following: nausea and/or emesis, photophobia and/or phonophobia, pain relieved by triptan or ergot, and no other explanation such as medication overuse or other cause.
      Headache Classification Subcommittee of the International Headache Society
      The International Classification of Headache Disorders. 2nd ed.
      Although chronic migraine is possible in this patient, her symptoms are concerning for secondary headache with new onset at age 30, no family history of migraine, and abnormal MRI findings. Her symptoms are not consistent with hemicrania continua, given the bilateral distribution of pain and lack of cranial autonomic symptoms such as lacrimation, nasal congestion, conjunctival injection, and facial flushing.
      Headache Classification Subcommittee of the International Headache Society
      The International Classification of Headache Disorders. 2nd ed.
      Idiopathic intracranial hypertension is unlikely; the presentation can vary widely but often includes papilledema on fundoscopic examination, a severe and lateralizing pulsatile headache, intracranial noises, double vision, and nausea.
      Headache Classification Subcommittee of the International Headache Society
      The International Classification of Headache Disorders. 2nd ed.
      Hypertrophic pachymeningitis, noted on review of the MRI, has a broad differential diagnosis including chronic meningitis (eg, infectious or autoimmune), intracranial hypotension, and carcinomatosis (eg, lymphoma or skull-based metastases). Our patient had weight loss but no other B symptoms such as fever or night sweats to suggest carcinomatosis. Chronic meningitis should be highly suspected given the MRI findings as well as her symptoms of headache, neck pain, blurry vision, nausea, and paresthesia. There are multiple infectious causes of chronic meningitis including tuberculosis, human immunodeficiency virus (HIV) infection, syphilis, listeriosis, brucellosis, and fungal, parasitic, and other chronic bacterial and viral etiologies. Noninfectious causes include sarcoidosis, systemic lupus erythematosus, granulomatous angiitis, Sjögren syndrome, or Behçet disease.
      A detailed review of symptoms was negative for additional symptoms except hair loss. She first noticed clumps of hair falling out 1 month after the onset of the illness, reporting nearly 50% volume loss in a diffuse pattern over the front and mid scalp; the hair loss had continued throughout her illness. On further examination, her hair was diffusely thinned, but no scaling or skin rash was observed. A hair pull test was positive for telogen. The challenge now was to determine the link between her alopecia and chronic meningitis.
      • 2.
        In view of the findings thus far, which one of the following is the most likely cause of the patient's hair loss?
        • a.
          Alopecia areata
        • b.
          Connective tissue disease
        • c.
          Androgenetic alopecia
        • d.
          Infection
        • e.
          Telogen effluvium
      Alopecia can be described as scarring or nonscarring and further classified as diffuse or focal. In general, alopecia can be caused by hormonal and genetic causes, medications, thyroid disorders, autoimmune disease, hypervitaminosis A, nutritional deficiencies (eg, zinc or biotin), and infection.
      • Harrison S.
      • Bergfeld W.
      Diffuse hair loss: its triggers and management.
      Alopecia areata is unlikely because it presents with focal patches of nonscarring hair loss in children and young adults. Our patient did not report rash or arthralgia, so a connective tissue disease would not be likely, although serologic tests would still be advised for a complete evaluation. Androgenetic alopecia presents with frontal sparing and thinning over the central part of the scalp. This pattern was not present, and the patient had no history of menstrual irregularities, acne, or hirsutism. Therefore, given the lack of another compelling explanation and the concern for chronic meningitis, an infectious etiology is considered most likely. The most common infectious causes include fungal (tinea capitis) and systemic (eg, HIV or syphilis) infections. Tinea capitis is a focal, scaling hair loss seen in children. Alopecia syphilitica presents in 4% to 12.5% of patients with secondary syphilis and hair loss.
      • Bi M.Y.
      • Cohen P.R.
      • Robinson F.W.
      • Gray J.M.
      Alopecia syphilitica—report of a patient with secondary syphilis presenting as moth-eaten alopecia and a review of its common mimickers.
      It is characterized by noninflammatory and nonscarring hair loss with either a moth-eaten or diffuse pattern. Telogen effluvium is a stress-related cause of diffuse hair loss. Although it may have contributed to her hair loss, the concern for chronic infection and the ongoing hair loss diminish the primacy of this diagnosis.
      Laboratory assessment (reference ranges provided parenthetically) revealed negative results for antinuclear antibody, an elevated C-reactive protein level (14 mg/L; ≤8 mg/L), and negative serologic results for HIV, West Nile virus, and Epstein-Barr virus. The rapid plasma reagin (RPR) titer was elevated at 1:64, and subsequent testing yielded positive results for syphilis. The patient was diagnosed as having secondary syphilis with alopecia syphilitica.
      • Bi M.Y.
      • Cohen P.R.
      • Robinson F.W.
      • Gray J.M.
      Alopecia syphilitica—report of a patient with secondary syphilis presenting as moth-eaten alopecia and a review of its common mimickers.
      • 3.
        Which one of the following is the criterion standard for the diagnosis of syphilis?
        • a.
          Darkfield microscopy
        • b.
          RPR
        • c.
          Fluorescent treponemal antibody absorption
        • d.
          Treponema pallidum particle agglutination
        • e.
          Serum IgG syphilis serology
      Treponema pallidum cannot be isolated in culture. The criterion standard, when feasible, is direct visualization by trained personnel. The thin corkscrew-shaped spirochete organisms (found in mucous membranes) can be seen with darkfield microscopy or direct fluorescent antibody test. However, in clinical practice, screening has typically been performed with nontreponemal serologic tests, including the Venereal Disease Research Laboratory (VDRL) test and RPR. If results are positive, confirmation by treponemal tests such as fluorescent treponemal antibody absorption or T pallidum particle agglutination would be performed. This traditional testing method is slow and labor intensive. High throughput laboratories have now adopted the reverse testing algorithm,
      Centers for Disease Control and Prevention (CDC)
      Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005-2006.
      which uses a Treponema-specific antibody screen by enzyme immunoassay or a multiplex flow immunoassay. A positive test result indicates exposure, and subsequent RPR helps determine disease activity. Rapid plasma reagin reports a titer that can help determine treatment effect or reinfection (4-fold titer decrease or increase, respectively). There are a few pitfalls to testing, including occasional false-negative results in severely immunosuppressed patients (eg those with advanced HIV infection).
      • Zetola N.M.
      • Engelman J.
      • Jensen T.P.
      • Klausner J.D.
      Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection.
      Furthermore, both syphilis IgG and IgM serology results may be negative in very early syphilis or, rarely, when patients have been treated successfully more than 10 years previously.
      • Workowski K.A.
      • Berman S.
      Centers for Disease Control and Prevention (CDC)
      Sexually transmitted diseases treatment guidelines, 2010.
      The patient's symptoms were consistent with neurosyphilis, which is strongly correlated with RPR titers greater than 1:32. A lumbar puncture showed a normal opening pressure of 21 cm H2O, and CSF analysis revealed 13.9 nucleated cells/μL (range, 0-5 cells/μL) with 92% lymphocytes and 8% monocytes; protein, 44 mg/dL (0-35 mg/dL); and glucose, 59 mg/dL with a serum glucose level of 94 mg/dL. A CSF VDRL test result was negative, and there was no bacterial or fungal growth from culture. Up to 70% of CSF VDRL test results are falsely negative in patients with neurosyphilis.
      • Jaffe H.W.
      • Larsen S.A.
      • Peters M.
      • Jove D.F.
      • Lopez B.
      • Schroeter A.L.
      Tests for treponemal antibody in CSF.
      This patient's previous treatment with ceftriaxone and azithromycin may have confounded the results of the CSF VDRL test as well. A patient with positive findings on syphilis serology and symptoms consistent with neurosyphilis may be diagnosed on the basis of pleocytosis (CSF lymphocyte count >5 cells/μL or >20 cells/μL with HIV coinfection due to an inherent pleocytosis from HIV)
      • Zetola N.M.
      • Engelman J.
      • Jensen T.P.
      • Klausner J.D.
      Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection.
      or by a protein concentration greater than 45 mg/dL.
      • Wharton M.
      • Chorba T.L.
      • Vogt R.L.
      • Morse D.L.
      • Buehler J.W.
      Case definitions for public health surveillance.
      Our patient had borderline CSF protein levels, but the lymphocytic pleocytosis with high serum RPR titer indicated neurosyphilis.
      • 4.
        In this patient with neurosyphilis, which one of the following would be the most appropriate treatment?
        • a.
          Penicillin G, 50,000 U/kg intravenously (IV) every 8 to 12 hours for 10 to 14 days
        • b.
          Penicillin G, 2.4 million U intramuscularly (IM) once
        • c.
          Penicillin G, 2.4 million U IM weekly for 3 weeks
        • d.
          Doxycycline, 100 mg orally twice daily for 4 weeks
        • e.
          Penicillin G, 3 to 4 million U IV every 4 hours or 24 million U continuous IV infusion for 10 to 14 days
      Penicillin G, 50,000 U/kg is the treatment of choice for congenital syphilis.
      • Workowski K.A.
      • Berman S.
      Centers for Disease Control and Prevention (CDC)
      Sexually transmitted diseases treatment guidelines, 2010.
      Penicillin G, 2.4 million U IM once, or the alternative doxycycline, 100 mg orally twice daily for 14 days, is the recommended treatment for early (primary, secondary, or latent for less than 1 year) syphilis.
      • Workowski K.A.
      • Berman S.
      Centers for Disease Control and Prevention (CDC)
      Sexually transmitted diseases treatment guidelines, 2010.
      Penicillin G, 2.4 million U IM weekly for 3 weeks, or alternatively doxycycline, 100 mg orally twice daily for 4 weeks, is the usual treatment for latent (tertiary) syphilis. Penicillin G, 24 million U continuous IV infusion for 10 to 14 days, is the most appropriate therapy for neurosyphilis. If adequate treatment duration is a concern, patients may be given additional penicillin G at 2.4 million U IM weekly for 1 to 3 weeks. Limited evidence suggests that ceftriaxone, 2 g/d IM or IV for 10 to 14 days can be used as an alternative in patients with penicillin allergy. Penicillin desensitization may be required if ceftriaxone is ineffective or if major cross-reactivity is present.
      The patient was admitted to the hospital the next day for administration of a loading dose of penicillin and initiation of continuous penicillin infusion. She received 2 doses of dexamethasone both to relieve her headaches and to minimize the risk of Jarisch-Herxheimer reaction. She tolerated these treatments well. She was treated with penicillin G, 24 million U/d by continuous infusion for 14 days, followed by benzathine penicillin, 2.4 million U IM once weekly for 3 weeks.
      • Ghanem K.G.
      Neurosyphilis: a historical perspective and review.
      • 5.
        Which one of the following is the most common feature of neurosyphilis?
        • a.
          Cognitive and behavioral disorders
        • b.
          Condylomata lata
        • c.
          General paresis
        • d.
          Tabes dorsalis
        • e.
          Argyll Robertson pupils
      In the postantibiotic era, mental and cognitive disorders have become the most common features of neurosyphilis, occurring in 85% of cases.
      • Mitsonis C.H.
      • Kararizou E.
      • Dimopoulos N.
      • et al.
      Incidence and clinical presentation of neurosyphilis: a retrospective study of 81 cases.
      These symptoms may develop within months of treponemal inoculation and include irritability, forgetfulness, personality changes, insomnia, and impaired memory. It is possible that the broad usage of antibiotics for unrelated conditions may lead to partially treated syphilis and an even more indolent course of disease. Condylomata lata is not a feature of neurosyphilis but can manifest during the secondary stage of syphilis with gray papules or plaques on the genitals, anus, and other moist areas. General paresis progresses between 15 and 20 years after initial infection and is manifested by confusion with delusions, depression, delirium, mania, and psychosis.
      • Ghanem K.G.
      Neurosyphilis: a historical perspective and review.
      Tabes dorsalis occurs in 3% to 9% of untreated patients, usually 20 to 25 years after initial infection.
      • Ghanem K.G.
      Neurosyphilis: a historical perspective and review.
      It involves ataxic gait, paresthesia, sharp (lightning) pain, bladder dysfunction, and optic atrophy. Neither general paresis nor tabes dorsalis are commonly seen in the postantibiotic era. Argyll Robertson pupils, with the classic findings of accommodation but no reaction to light, are also rarely seen in the current postantibiotic era.
      Additional testing for sexually transmitted infections was also negative for hepatitis B, hepatitis C, gonorrhea, and chlamydia. Ophthalmology examination revealed no evidence of iritis. The patient's boyfriend, who was asymptomatic, was tested for syphilis and was found to have a positive RPR at a titer of 1:32. He has since undergone treatment. By 6 weeks after treatment, our patient reported complete resolution of her headaches and cessation of hair loss. Her follow-up will include CSF examinations every 6 months until CSF abnormalities resolve and serum RPR titers show a 4-fold decrease, which correlates with resolution of neurosyphilis.
      • Ghanem K.G.
      Neurosyphilis: a historical perspective and review.

      Discussion

      The stages of syphilis are broadly categorized as early, latent, and late. Early syphilis can be primary, which is manifested by chancre and regional lymphadenopathy, or secondary, which variably involves a diffuse macular or papular rash affecting the palms and soles, condylomata lata, fever, headache, alopecia, and anorexia. Syphilitic meningitis typically occurs in early syphilis and has either an acute or chronic presentation, the latter perhaps being more common in partially treated infection. Latent syphilis, occurring after initial infection, involves an asymptomatic phase with ongoing serologic evidence of infection. Finally, late or tertiary syphilis includes gummas, cardiovascular involvement such as aortitis, and central nervous system disease including general paresis and tabes dorsalis.
      The highest rates of syphilis in the United States are in urban areas and southern states, along with a resurgence in HIV.
      Centers for Disease Control and Prevention (CDC)
      Primary and secondary syphilis—United States, 2003-2004.
      Men who have sex with men account for 65% of all cases of syphilis.
      Centers for Disease Control and Prevention (CDC)
      Primary and secondary syphilis—United States, 2003-2004.
      Coinfection with HIV is alarmingly high at 25%.
      Centers for Disease Control and Prevention (CDC)
      Primary and secondary syphilis among men who have sex with men—New York City, 2001.
      Coinfection with HIV and the overuse of antibiotics, with subsequent partial treatment of treponemal infection, may be contributing to changes in the presentation of syphilis.
      • Zetola N.M.
      • Engelman J.
      • Jensen T.P.
      • Klausner J.D.
      Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection.
      Human immunodeficiency virus infection may accelerate and change the general course of syphilis, including an increased incidence of neurosyphilis and ocular syphilis.
      • Zetola N.M.
      • Engelman J.
      • Jensen T.P.
      • Klausner J.D.
      Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection.
      The classic late presentations of neurosyphilis have migrated toward a predominance of cognitive impairment and behavioral symptoms.
      • Mitsonis C.H.
      • Kararizou E.
      • Dimopoulos N.
      • et al.
      Incidence and clinical presentation of neurosyphilis: a retrospective study of 81 cases.
      The reverse screening method detects antibodies to determine exposure, but subsequent RPR is required to determine disease activity and monitor successful treatment. Negative results on CSF VDRL testing are common and do not exclude neurosyphilis in a patient with syphilis-positive serology and suggestive symptoms; thus, CSF pleocytosis and a high protein level also indicate neurosyphilis. Brain MRI can be helpful by demonstrating pachymeningeal enhancement in syphilitic meningitis or signs of stroke or broader parenchymal involvement in late syphilis.

      References

        • Headache Classification Subcommittee of the International Headache Society
        The International Classification of Headache Disorders. 2nd ed.
        Cephalalgia. 2004; 24 (Available at:): 1-150
        • Harrison S.
        • Bergfeld W.
        Diffuse hair loss: its triggers and management.
        Cleve Clin J Med. 2009; 76: 361-367
        • Bi M.Y.
        • Cohen P.R.
        • Robinson F.W.
        • Gray J.M.
        Alopecia syphilitica—report of a patient with secondary syphilis presenting as moth-eaten alopecia and a review of its common mimickers.
        Dermatol Online J. 2009; 15: 6
        • Centers for Disease Control and Prevention (CDC)
        Syphilis testing algorithms using treponemal tests for initial screening—four laboratories, New York City, 2005-2006.
        MMWR Morb Mortal Wkly Rep. 2008; 57: 872-875
        • Zetola N.M.
        • Engelman J.
        • Jensen T.P.
        • Klausner J.D.
        Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection.
        Mayo Clin Proc. 2007; 82 ([published correction appears in Mayo Clin Proc. 2007;82(11):1434]): 1091-1102
        • Workowski K.A.
        • Berman S.
        • Centers for Disease Control and Prevention (CDC)
        Sexually transmitted diseases treatment guidelines, 2010.
        MMWR Recomm Rep. 2010; 59 ([published correction appears in MMWR Recomm Rep. 2011;60(1):18]): 1-110
        • Jaffe H.W.
        • Larsen S.A.
        • Peters M.
        • Jove D.F.
        • Lopez B.
        • Schroeter A.L.
        Tests for treponemal antibody in CSF.
        Arch Intern Med. 1978; 138: 252-255
        • Wharton M.
        • Chorba T.L.
        • Vogt R.L.
        • Morse D.L.
        • Buehler J.W.
        Case definitions for public health surveillance.
        MMWR Recomm Rep. 1990; 39: 1-43
        • Ghanem K.G.
        Neurosyphilis: a historical perspective and review.
        CNS Neurosci Ther. 2010; 16: e157-e168
        • Mitsonis C.H.
        • Kararizou E.
        • Dimopoulos N.
        • et al.
        Incidence and clinical presentation of neurosyphilis: a retrospective study of 81 cases.
        Int J Neurosci. 2008; 118: 1251-1257
        • Centers for Disease Control and Prevention (CDC)
        Primary and secondary syphilis—United States, 2003-2004.
        MMWR Morb Mortal Wkly Rep. 2006; 55: 269-273
        • Centers for Disease Control and Prevention (CDC)
        Primary and secondary syphilis among men who have sex with men—New York City, 2001.
        MMWR Morb Mortal Wkly Rep. 2002; 51: 853-856