Headache can appear at any stage of HIV infection and may be primary or secondary. Primary headaches occur in the acute illness stage associated with HIV-1 seroconversion and accompany acute, recurrent, or chronic aseptic meningitis or emerge in the late stage as late stage HIV-headache without pleocytosis. Secondary HIV-related headaches are caused by opportunistic infections and tumors resulting from medications used to treat HIV-1 infections and accompanying immune restoration inflammatory syndrome.
Headache appearing in an HIV-infected person requires the same differential diagnostic skills as with all other headaches, and opportunistic infections and neoplasms must constantly be kept in mind. In the early HIV stage, migraine and tension-type headaches predominate, while sinus infections are not uncommon in those with CD4 counts above 200/mm2. For those with counts below 200/mm2, the three most common opportunistic conditions that cause headaches are cryptococcal meningitis, toxoplasma encephalitis, and primary CNS lymphoma; less frequent infections that cause headaches include bacterial meningitis, viral encephalitis, coccidioidomycosis, histoplasmosis, tuberculosis, nocardiosis, and pyogenic brain abscesses. Failure to maintain a high index of suspicion can be fatal. In patients with a CD4+ T cell count below 200/mm3, a serum cryptococcal antigen assay should be obtained to screen for cryptococcal disease. A negative result essentially excludes cryptococcal meningitis; a positive result must be followed up with a lumbar puncture and assay for cryptococcal antigen in the CSF.
Primary HIV-related Headaches
Headaches often occur as part of the acute mononucleosis-like illness experienced as part of the primary infection with HIV-1 [1, 2]. This acute illness, occurring in 53% to 93% of individuals, develops two to four weeks after HIV-1 exposure and lasts one to two weeks. The headaches these patients develop range from febrile headaches associated with the systemic viral infection, to headaches associated with retro-orbital pain, photophobia, and meningeal signs reflecting acute viral lymphocytic meningitis. Acute aseptic meningitis has been estimated to occur in 1% to 2% of all primary HIV-1 infections. Other neurologic complications that may accompany the primary infection with HIV-1 include Bell palsy, acute encephalitis, acute demyelinating polyneuropathy, and brachial neuritis. Aseptic meningitis is often self-limited but can recur at any time following the primary infection. HIV-infected individuals can suffer from chronic headaches that last for months.
At any stage of the disease following initial infection, an acute or chronic headache can develop in the presence of an unexplained lymphocytic pleocytosis. The acute headache resembles meningitis associated with the primary infection and is associated with fever, meningeal signs, and cranial nerve palsies. The cerebrospinal fluid lymphocytic pleocytosis ranges from 20 cells/mm3 to 300 cells/mm3 and is often associated with an elevated cerebrospinal fluid protein. The chronic headaches are holocephalic, low-to-moderate in intensity, and resemble tension-type headaches. These patients may also have an unexplained cerebrospinal fluid lymphocytosis, but the increase in CSF white cells, which is rarely above 40 cells/mm3, is not as dramatic as in those patients with the acute aseptic meningitis. This finding is not specific for headache, as mild lymphocytic pleocytosis with accompanying elevated cerebrospinal fluid protein can also be seen in asymptomatic HIV-infected individuals without headaches.
Patients in late stages of the HIV disease may also present with a new-onset headache without an identifiable etiology. These patients usually complain of holocephalic pain and frequently experience photophobia. A defining feature of the headache is the absence of CSF pleocytosis and may represent “aseptic” meningitis in a lymphocyte-depleted patient.
At any stage of the disease following initial infection, an acute or chronic headache can develop in the presence of an unexplained lymphocytic pleocytosis. The acute headache resembles meningitis associated with the primary infection and is associated with fever, meningeal signs, and cranial nerve palsies. The cerebrospinal fluid lymphocytic pleocytosis ranges from 20 cells/mm3 to 300 cells/mm3 and is often associated with an elevated cerebrospinal fluid protein.
Opportunistic Infections and Tumors
Two studies analyzed headache characteristics and associated symptomatology in HIV-infected patients presenting with an opportunistic infection or tumor. Headaches secondary to an opportunistic infection causing meningitis were constant, gradual in onset, and associated with fever, nausea, vomiting, and photophobia. Headaches secondary to mass lesions were variable in onset and quality, and associated with focal neurologic deficits and confusion. However, considerable variability occurs, and a fulminant opportunistic disease can arise in patients with mild or no symptoms, including the absence of headache [3, 4].
Headaches Due to Medications Used in HIV-1 Infection
Medications used to treat either HIV-1 disease or its complications can cause headaches. In a double-blind, placebo-controlled trial of zidovudine in patients with AIDS or AIDS-related complex, the incidence of headache was not significantly different between groups (approximately 40%), but more patients reported moderate or severe headache on zidovudine (43%) than placebo (24%). One study found that 16% of pain patients suffered from zidovudine-induced headaches, but most of their patients’ headaches gradually subsided over a period of weeks to months after starting the medication. Headache occurs in greater than 5% of patients receiving other nucleoside/nucleotide reverse transcriptase inhibitors such as abacavir, stavudine, or tenofovir.
Nervous system symptoms, including headache, appear to be the most common adverse events reported with efavirenz, a non-nucleoside reverse transcriptase inhibitor. Headache was reported in less than 5% of patients receiving nelfinavir-containing regimens.
Headache was among the most frequent adverse events associated with some new protease inhibitors, such as amprenavir and lopinavir/ritonavir. However, use of lopinavir/ritonavir in ‚Ä®six double-blind trials noted an adverse event of headache between 0.06% and 7%.
Causes of Headaches in Early or Latent HIV Disease
- Acute meningitis associated with HIV-1 seroconversion
- Acute, recurrent, or chronic “aseptic” meningitis
- Syphilitic meningitis
- Drug-induced headache
- Medication overuse headache or withdrawal headache
- Tension-type headache
- Depression or other psychiatric illnesses
- Inflammation of the cranial nerves (e.g., Herpes zoster)
Causes of headache in late HIV-1 disease include the opportunistic infections and tumors detailed above, as well as focal brain lesions, including toxoplasmosis encephalitis, primary central nervous system lymphoma, progressive multifocal leukoencephalopathy, Cryptococcoma, and Candida abscess. Headache etiologies in late HIV-1 disease include diffuse brain lesions, Cytomegalovirus encephalitis, herpes simplex virus encephalitis, toxoplasmosis encephalitis, and HIV-associated dementia. A positive result must be followed up with a lumbar puncture and assay for cryptococcal antigen in the CSF. Successful management of cryptococcal meningitis hinges on controlling intracranial pressure (ICP) with serial lumbar punctures or, in severe cases, placement of an intraventricular drain (elevated ICP is not a contraindication for lumbar puncture in this setting). Patients should be treated with a combination of amphotericin B (0.7 mg/kg/day I.V.) and flucytosine (100 mg p.o.) for 14 days, followed by fluconazole (400 mg p.o., q.d.) for 8 weeks, and finally fluconazole prophylaxis (200 mg p.o., q.d.) indefinitely or until substantial immune recovery has occurred.
Other useful CSF tests are cell count; chemistries; Venereal Disease Research Laboratory (VDRL) testing; cytology; stains and cultures for specific suspected pathogens; PCR testing for CMV, HSV, and JC virus for progressive multifocal leukoencephalopathy (PML); and Epstein-Barr virus testing for primary CNS lymphoma. Neuroimaging with a CT scan or MRI should be performed before lumbar puncture to rule out a mass lesion, particularly in a patient with focal neurologic signs.
Drug-induced headaches may be caused by zidovudine, analgesics, recreational drugs, and medication overuse headache. Primary and other types of headaches are not unknown, including tension-type headache, migraine, depression, and post lumbar puncture headache.
Treatment of Headache in HIV/AIDS
No effective therapy is known for the acute aseptic meningitis associated with HIV-1 infection. Treatment of 11 patients with zidovudine who presented with the clinical illness characteristic of primary HIV-1 infection showed no improvement of symptoms or prevention of persistent infection . However, this condition is self-limited and can be treated symptomatically with antipyretics and analgesics. Recommendations for the treatment of chronic headache associated with a cerebrospinal fluid lymphocytic pleocytosis are based on anecdotal experience. Some clinicians have found that a two-week course of oral prednisone, starting at 60 mg a day followed by a taper, reduces the headache severity in many of these patients. No adverse events, such as worsening immunosuppression, have been noted with the use of steroids. Moreover, prednisone has been used with tolerable side effects in other HIV-associated diseases, such as HIV-associated myopathy and pneumocystis pneumonia. Alternative treatments exist, although low-dose amitriptyline, starting at 10 mg each evening, may be effective in ameliorating these chronic headaches.
Headaches occurring in the setting of opportunistic infections require treatment of the underlying condition, as do headaches related to opportunistic tumors. Zidovudine-induced headaches may require switching to an alternative antiretroviral agent. If the headache is not debilitating and the patient is willing, he or she may wish to wait several weeks or months before beginning a prescription medication because these headaches tend to recede with time.
In patients with previously treated syphilis, any unusual aspect of the history, neurologic examination, or diagnostic studies should prompt retesting and possible treatment. Intravenous penicillin is recommended if there is clinical or laboratory evidence of neurosyphilis (e.g., cerebrospinal fluid-VDRL reactivity, change in serum rapid plasma reagin titers, cerebrospinal fluid hypoglycorrhachia, number of cerebrospinal fluid lymphocytes, and meningeal enhancement on head MRI with gadolinium). Despite this approach, a high level of suspicion is necessary because the serodiagnosis of syphilis may be artificially negative.
The treatment of migraine and tension-type headaches is similar to that in the general medical population. The same principles of education, modifying risk factors, abortive treatment, prophylactic treatment, and developing a treatment plan agreeable to both patient and physician apply. Several factors influence the choice of treatment, including the severity of headache, the frequency of headache, and the presence of comorbid medical and psychiatric conditions, patient preferences, and access to care, including insurance coverage. Recognizing and referring or treating patients with concurrent mood and anxiety disorders may be the most important aspect in the management of many of these patients.
Because many medications used to treat tension-type and migraine headaches have comparable efficacy, the governing principle of prioritizing therapy is based primarily on side-effect profiles. For example, antidepressants such as amitriptyline, with its sedative properties, may not be appropriate for those patients with fatigue and low energy levels; selective serotonergic antidepressants, such as fluoxetine, sertraline, and paroxetine, with their less sedating properties, would likely serve these patients better. Conversely, serotonergic antidepressants, with their associated side effects of gastrointestinal distress and diarrhea, would prove less useful in patients suffering from chronic diarrhea.
The physician must guard against medication abuse and avoid precipitating analgesic-overuse syndromes by instructing patients to limit caffeine consumption and the use of commonly prescribed analgesics, and restricting the use of butalbital and analgesic-containing mixtures to 10 or fewer doses per week. Narcotics should remain a “last resort” alternative in medical management in all cases. In those patients with chronic daily headaches from polysubstance abuse, inpatient withdrawal may be required if outpatient therapy seems unrealistic. A coordinated and detailed treatment plan through a drug rehabilitation unit is essential for the long-term success in treating the headaches secondary to illicit substances.
Keep in mind that interactions occur between drugs used to treat HIV-associated diseases and drugs used to treat headaches. Although the clinical significance of most offensive interactions is unknown, it may be prudent to avoid combinations that are known to cause interactions, given the number of alternative headache medications available. For example, the most common interaction is between zidovudine and acetaminophen, which decreases blood levels of zidovudine. Ratonavir has several significant drug interactions, including increasing the plasma concentrations of analgesics, antidepressants, calcium channel blockers, and ergotamine derivatives. Aspirin or non-steroidal anti-inflammatory agents should be encouraged for the chronic treatment of headaches, even in HIV/AIDS patients.
- HIV/AIDS is a lentivirus caused complex disease state which is highly stage dependent.
- Knowledge of the CD4 status of the patient is imperative to know the diagnostic possibilities.
- Almost half of the highly prevalent pain conditions (also stage dependent) are neuropathic, with neuropathy and headaches being most common.
- Opportunistic and neoplastic conditions should be high on the differential diagnostic list but other conditions other than HIV/AIDS may contribute to pain states.
- While HAART remains the mainstay of treatment for the primary disorder, relief of pain follows the WHO ‚Äúladder‚Äù for pain management.
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- T indall B, Imrie A, Donovan B, Penny R, Cooper DA. Primary HIV infection. In: Sande MA, Volberding PA, editors. The medical management of AIDS. 3rd ed. Philadelphia: WB Saunders; 1992:67-86.
- Goldstein J. Headache and acquired immunodeficiency syndrome. Neurol Clin. 1990; 8:947-60.
- Lipton RB, Feraru ER, Weiss G, et al. Headache in HIV-1-related disorders. Headache. 1991; 31:518-22.
- Tindall B, Gaines H, Imrie A, et al. Zidovudine in the management of primary HIV-1 infection. AIDS. 1991; 5:477-84.
- Fung HB, Stone EA, Piacenti FJ. Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection. Clin Ther. 2002; 24(10):1515-48.