Headache Currents

HEADACHE CURRENTSCLINICAL REVIEW

Clinical Aspects of Headache in HIV

Huma U. Sheikh, MD; Tracey A. Cho, MD

and even fewer studies that determine the natural progression of

headaches in the era of combination antiretroviral therapy
(cART).1

Background.Headaches are commonly seen in those

patients with human immunodeficiency virus (HIV) and are the
most common form of pain reported among HIV patients.
There have been relatively few studies attempting to determine
the rates and phenotypes of the headaches that occur in patients
with HIV.
Discussion.Patients with HIV are susceptible to a much
broader array of secondary headache causes, sometimes with
atypical manifestations due to a dampened inflammatory
response. The investigation of a headache in the HIV patient
should be thorough and focused on making sure that secondary
and HIV-specific causes are either ruled out or treated if present.
Conclusion.An effective treatment plan should incorporate
the use of appropriate pharmacological agents along with the
integration of non-pharmacological therapies, such as relaxation
and lifestyle regulation. When treating for headaches in patients
with HIV, it is important to keep in mind comorbidities and
other medications, especially combination antiretroviral therapy.
For those with complicated headache histories, referral to a
specialized headache center may be appropriate.
Key words: HIV,
opportunistic

headache,

preventive,

abortive,

ETIOLOGY

migraine,

EPIDEMIOLOGY
It is estimated that over 1 million people in the United States are
infected with the human immunodeficiency virus (HIV), the
causative agent of acquired immune deficiency syndrome
(AIDS).1 About 65% of those were non-whites, and almost half
were men who have sex with men.2
In the last 10-15 years, with advances in antiretroviral treatment, most people with access to care are able to survive longer
with HIV, without converting to AIDS. However, with patients
living with HIV for longer periods, there has been a rise in other
comorbid conditions, including headaches. In fact, headaches are
commonly seen in those patients with HIV, with some estimates
as high as 38-61%.1 Headache is the most common form of pain
reported among HIV patients.3,4 Despite its prevalence, there
have been relatively few studies attempting to determine the rates
and phenotypes of the headaches that occur in patients with HIV,
From the Department of Neurology, Harvard Medical School, John Graham Headache Center,
Brigham and Womens Faulkner Hospital, Boston, MA, USA (H.U. Sheikh); Department of
Neurology, Harvard Medical School, Neurology-Infectious Diseases Program, Massachusetts
General Hospital, Boston, MA, USA (T.A. Cho).
Address all correspondence to T.A. Cho, Department of Neurology, Harvard Medical School,
Neurology-Infectious Diseases Program, Massachusetts General Hospital, 55 Fruit Street,
Boston, MA, 02114, USA.
Accepted for publication February 26, 2014.
.............
Headache
2014 American Headache Society

Secondary Headaches
In any patient presenting with a new headache, the most important aspect is looking for clues that might lead one to suspect a
secondary cause of the headache. This can include potentially
life-threatening conditions, including a tumor, ischemic stroke,
or hemorrhage. It is important to note that patients with HIV
can have many of the same conditions that afflict patients
without HIV. In most cases, the cause of headaches in patients
with HIV will be similar to those without HIV.5 However, especially with advanced infection, there are causes that are specific to
patients with HIV that may require specific treatment.
HIV easily crosses the blood brain barrier that makes neurological manifestations of initial and chronic infection very
common.1 The incidence of opportunistic central nervous system
(CNS) infections and neoplasms increases significantly when the
CD4 counts fall to less than 200 cells/L.1
While patients with well-controlled HIV may have similar
causes of headache to non-infected patients, those with advanced
HIV are susceptible to a much broader array of secondary headache causes, sometimes with atypical manifestations due to a
dampened inflammatory response. The onset of new headaches
in a patient with HIV thus requires the treating physician assess
the level of immunocompromise and then rule out opportunistic
infections for those with advanced disease (see Table 1).
In developed countries, the most common causes of focal CNS
lesions in advanced HIV include cerebral toxoplasmosis (see
Fig. 1), primary CNS lymphoma, and progressive multifocal leukoencephalopathy (PML). These are usually associated with focal
symptoms and signs, although headache and confusion may be
the only symptoms.
Cytomegalovirus encephalitis causes diffuse encephalitis and
ventriculitis in profoundly immunocompromised patients
(usually CD4 <50 cells/L). Cryptococcus is the most common
cause of meningitis in these patients and often presents with
headache and confusion without prominent meningismus (see
Fig. 2).
In the appropriate context, neurosyphilis and tuberculosis may
also cause either meningitis or focal brain lesions.6 As antiretroviral treatments have lead to improved immune restoration, a
unique phenomenon has emerged in which patients started on
effective cART experience a worsening due to the inflammatory
.............
Conflict of Interest: None.

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940 | Headache | May 2014

Table 1.Neurological Complications of HIV by Location Within Brain

Focal
Toxoplasma encephalitis
Primary CNS lymphoma
PML
Bacterial abscess due to atypical organism
Tuberculoma
HIV-associated stroke

Diffuse

Meninges

HIV-associated dementia
CMV encephalitis
VZV encephalitis
Post-infectious encephalomyelitis

Cryptococcal meningitis
Tuberculous meningitis
HIV meningitis
Other fungal meningitis (Histoplasma, Coccidiodes)
Meningovascular syphilis

PML = progressive multifocal leukoencephalopathy; HIV = human immunodeficiency virus; CNS = central nervous system; CMV = cytomegalovirus;
VZV = varicella zoster virus.

reaction from a reconstituted immune response, termed immune

reconstitution inflammatory syndrome (IRIS). This may occur in
response to a known opportunistic infection or to a previously
asymptomatic infection.
In the brain, IRIS most commonly occurs with cryptococcal
meningitis, PML, tuberculosis, HIV, and occasionally toxoplasma. New headaches in a patient recently started on cART
should prompt consideration of IRIS and appropriate work-up
including imaging.
Apart from opportunistic infections, HIV may cause several
neurological complications either directly or through stimulation
of an inappropriate immune reaction. Aseptic meningitis due to
HIV typically occurs at initial seroconversion with CNS invasion
but may occur in the setting of viral rebound because of nonadherence or viral resistence to cART.1,6
HIV can also cause a chronic headache that at times may be
associated with cerebrospinal pleocytosis, although low-grade
meningitis is common in HIV patients even without headache.6
Rarely, early HIV infection has been associated with primary
angiitis of the CNS.7,8 Patients with HIV may also be more prone
to headaches from other comorbid conditions or medications.
Headache may occur as a side effect of cART. While many
medications can cause headaches, the nucleoside analog reverse
transcriptase inhibitor zidovudine has a high incidence of headache in the first few weeks after initiation.3 These secondary
causes should be evaluated before diagnosing someone with a
primary headache disorder.
Primary Headaches
Primary headache disorders also occur in large proportions in
patients with HIV.1 The most common types of headaches found
in these patients are migraines and tension-type headaches, and
less commonly cluster headaches.1,3-5,8-11 One study found that
almost half of patients with HIV suffered from headaches, of
which most were of the migrainous phenotype.1
There have been only a few studies looking at the rate of these
primary headache disorders in patients with HIV, including
those on cART. Although not a consistent finding, some studies

have found that there is a relation between CD4 counts and

headache. Patients with more advanced disease were more likely
to have more frequent and severe headaches, independent of
opportunistic infections.1,9-11

WORK-UP
Although most causes of headache are benign, certain features
may point to more ominous etiologies. Overall, the yield of
testing (especially imaging) is low with headaches; however, in
certain settings, it is an important diagnostic method for diagnosing secondary causes.12 The mnemonic created by Dr. David
Dodick, SNOOP, refers to features that should prompt further
evaluation for secondary causes: the presence of systemic symptoms such as fevers or weight loss, or secondary risk factors, like
immunosuppression or chronic steroid therapy; neurological signs
like lowered level of consciousness or focal deficits on exam; onset
of headache that is sudden or quickly builds up; older age at onset
(50 years); and pattern, or a change in the frequency or features
in someone with a previous history of headaches.13
Some other concerning features in new onset headaches to be
aware of include: thunderclap or worst headache, side-locked,
or headaches associated with Valsalva maneuvers, vomiting,
cough, sexual activity, or those that awaken one from sleep.12,14
The physical exam can provide some important clues and should
be done in every patient at each visit. Anyone with concerning
signs, including papilledema, temporal tenderness, personality
changes, or new unilateral findings should have further
testing.12-14 Headaches associated with seizures or after trauma
should also be worked up further.
The American Academy of Neurology recommends imaging
in those with rapidly increasing frequency, lack of coordination,
localizing signs or abnormal examination, and headaches that
awaken someone from sleep.7,12,14 This is not a complete list, and
it is important to use clinical judgment when assessing patients
with headaches. Patients with HIV constitute a special population and warrant imaging with new headaches, regardless of age
or CD4 count, although suspicion should be higher with lower
CD4 count.

941 | Headache | May 2014

Headache Currents

Fig 1.Toxoplasma encephalitis. A 30-year-old woman with no known medical history presented with 2 weeks of worsening bifrontal headaches
and gait difficulty. On exam, she was sleepy and inattentive with mild left facial weakness and pathologically increased left reflexes. Magnetic
resonance imaging axial fluid attenuated inversion recovery (A,C) and T1 post-contrast (B,D) imaging demonstrated multifocal mass lesions with
heterogeneous enhancement and surrounding edema. Serum human immunodeficiency virus (HIV) enzyme-linked immunosorbent assay was
positive with CD4 count of 63 cells/L and HIV viral load 290,000 copies/L. Serum toxoplasma immunoglobulin G was positive, and she
responded to empiric treatment for toxoplasmosis.

The timing and choice of studies depends on the onset and

severity. For acute severe headache or rapid neurological decline,
the work-up begins with a computed tomography (CT) scan,
which is rapidly available, will detect most abnormalities, and is
preferred for detecting bony abnormalities and acute blood,
including subarachnoid hemorrhage.12-14
If headaches are subacute, magnetic resonance imaging (MRI)
is more sensitive, especially for detecting posterior fossa abnormalities, thrombosis, subdural and epidural hematomas, meningeal disease, pituitary pathology, and findings associated with low
cerebrospinal fluid (CSF) pressure.12 MRI is also preferred in

young children and pregnant women because of the radiation

exposure risk with CT scans. A lumbar puncture is essential when
disorders of the CSF are suspected, including meningitis and
disorders of CSF pressure.6,13-15
Because of the possibility of herniation from removal of CSF
below a mass lesion, CT should be performed prior to lumbar
puncture in patients with altered mental status, seizures, papilledema, or focal signs. Immunocompromise, and specifically
HIV, is also a reason to obtain imaging in advance, as patients
may have subtle findings despite significant intracranial pathology or more than 1 intracranial process simultaneously.16 Even

942 | Headache | May 2014

Headache Currents

Fig 2.Cryptococcal meningitis. A 45-year-old man with no known medical history presented with 2 weeks of mild headache and was evaluated
at multiple institutions with reportedly normal computed tomography. Over 2 days, he developed nuchal rigidity and a more severe headache. On
exam, he had a fever of 102.9F, mildly depressed arousal, but otherwise normal neurological exam. Magnetic resonance imaging axial fluid
attenuated inversion recovery revealed diffuse sulcal increased T2 signal (A), with corresponding sulcal enhancement on axial T1 post-contrast (B).
Serum human immunodeficiency virus (HIV) enzyme-linked immunosorbent assay was positive with CD4 count 23 cells/L and HIV viral load
5500 copies/L. Cerebrospinal fluid revealed opening pressure of 50 mm of water, glucose 21 mg/dL, total protein 185 mg/dL, white blood cell
count (WBC) 53 cells/L (89% lymphocytes), positive India ink stain, and cryptococcal antigen positive at 1:4096. He responded to treatment for
Cryptococcus but ultimately required a ventriculoperitoneal shunt for persistently elevated intracranial pressure.

after a normal CT or MRI, lumbar puncture is usually indicated

for patients with the worst headache of their life to rule out
subarachnoid hemorrhage.14,15 Patients with HIV may have
subtle findings detectable only on MRI, so a negative CT cannot
exclude intracranial pathology in these patients. Patients with
advanced HIV and new headaches always require an LP since
they can present with meningitis with few other symptoms as
they may not be able to mount an immune response.
Depending on history, other tests may be warranted, including
magnetic resonance angiogram (MRA) to look for signs of reversible cerebrovasoconstriction syndrome, which can present as
recurrent thunderclap headaches. An magnetic resonance venogram (MRV) may be necessary to look for venous thrombosis
that is more frequent in pregnant women or those that have
coagulation problems. Other specific tests should be directed at
specific secondary causes depending on history and results of
initial imaging and CSF studies (see Table 2).

TREATMENT
An effective treatment plan should incorporate the use of appropriate pharmacological agents along with the integration of
non-pharmacological therapies, like relaxation and lifestyle
regulation.17-19 If the headaches are secondary once the underlying
problem is treated, the headache can be symptomatically treated
with similar medications as the primary headaches. For example,

Table 2.Select Studies to Evaluate for CNS Opportunistic

Infections in HIV
Blood/Serum
Routine
HIV viral load
CD4 cell count and percentage
Complete blood count with
differential
Creatinine and BUN
Liver function tests
Targeting specific diseases
Toxoplasma serology
Treponemal antibody
Interferon release assay (TB)

CSF
Opening pressure
Glucose
Total protein
Total nucleated cell count
Red blood cell count
Cryptococcal antigen
India ink stain
Fungal culture
AFB stain
Mycobacterial culture
PCR for JC virus, VZV, HIV,
EBV, CMV
VZV antibodies
Cytology
Flow cytometry

CNS = central nervous system; CSF = cerebrospinal fluid; HIV =

human immunodeficiency virus; BUN = blood urea nitrogen;
AFB = acid fast bacilli; PCR = polymerase chain reaction; JC =
JC virus; CMV = cytomegalovirus; VZV = varicella zoster virus;
EBV = Epstein Barr virus.

Headache Currents

943 | Headache | May 2014

Table 3.Selected Drug Choices in Migraine and HIV

Preferred Migraine
Drugs in HIV
Abortive
Triptans
Anti-emetics
NSAIDs
Preventive
Tricyclic antidepressants
Valproate
Topiramate
Botulinum toxin

Second-Line or Contraindicated
Migraine Drugs HIV
Ergots (contraindicated)
Proton pump inhibitors (with NSAIDs)
Corticosteroids (likely safe if CD4 >200)
Beta-blockers (second-line)
Gabapentin (second-line)
Serotonin/norepinephrine reuptake
inhibitors (second-line)
Calcium channel blockers (second-line)
Magnesium-containing regimens

HIV = human immunodeficiency virus; NSAID, non-steroidal antiinflammatory drug.

headaches secondary to an opportunistic CNS infection should be

treated with appropriate antimicrobials. If a patient continues to
have headaches after treatment, they may be treated with either
abortives or migraine preventives, if they become chronic.
When choosing a regimen for headache treatment in patients
with HIV, comorbidities and other medications, especially cART,
must be carefully considered. A typical cART regimen is made up
of at least 3 medications, usually consisting of some combination
of nucleoside reverse transcriptase inhibitors (NRTIs), nonNRTIs (NNRTIs), and protease inhibitors (PIs), most of which
are metabolized by cytochrome P450.20 Some of the known
interactions with medications used for treatment of headache are
reviewed later. A comprehensive review of possible interactions
should be performed before starting a new headache medication
for patients on cART (see http://guideline.gov/content.aspx?
id=15721 or http://www.hiv-druginteractions.org/Interactions.
aspx). Table 3 summarizes headache drug choices in patients with
HIV.
Specific acute treatments for migraine include triptans and
ergots.21,22 Triptans are relatively safe for use in HIV patients.
They should be avoided, however, in patients with a history of
stroke, coronary artery disease, and peripheral vascular disease,
which may occur at earlier ages in patients with chronic HIV.21
Triptans are also contraindicated in patients with hepatic impairment (hepatitis C is a common coinfection with HIV), renal
impairment, and hemiplegic migraines. Their safety for basilartype migraine remains debated.17
Severe ergot reactions have been associated with certain antiretroviral therapy (ART) agents. There have been reports of fatal
and non-fatal cases of ergotism used in patients who are also
taking PIs.20,23 Interactions with NNRTIs have also been implicated. Symptoms of ergotism, include seizures, paresthesias,
psychosis, vomiting, and possible gangrene due to vasoconstric-

tion of blood vessels.22 As there are other available abortive

agents, ergots should be completely avoided in HIV patients on
ART.
Other available abortive treatments include non-steroidal antiinflammatory drugs (NSAIDs) and neuroleptics/anti-emetics,
most of which are D2 receptor antagonists to treat nausea.17
Intravenous formulations are frequently used in the emergency
setting but are available in tablets and suppositories for use at
home.17 Prochlorperazine and metoclopramide are 2 of the more
commonly used anti-emetics.24 Other less commonly used medications are barbiturates, antihistamines, anticonvulsants, and
opioids as a last resort.17,24,25
In general, non-specific medications can be utilized for mildto-moderate level headaches but should be selected based on the
patients medical history. For example, NSAIDs should be
avoided in patients with gastric ulcers or other gastrointestinal
(GI) disturbances.17 Some may decide to take NSAIDs with a
proton-pump inhibitor (PPI) to prevent GI upset, but they
should be careful of interactions with PPIs and some cART
medications.
The concurrent use of PPIs and atazanavir is associated with
significant reductions in atazanavir concentrations.20,23 Therefore, all PPIs (such as omeprazole, lansoprazole, esomprazole,
rabepraolze) should be avoided with concurrent atazanavir
therapy. PPIs should also be avoided in patients receiving the
NNRTI delavirdine as well.23
While corticosteroids are frequently used a salvage abortive
agent for refractory headache, they should be used with caution
in patients with HIV as they can lead to further immunosuppression. Short courses in patients with CD4 cell counts above
200 cells/L are probably safe.
Preventive therapy for migraine is widely underused.25,26
The aim of preventive therapy is to decrease the frequency
and intensity of migraines. Preventative therapy is typically
started in patients who have chronic headache, which implies
a headache frequency greater than 15 headache days per
month.25
Although choosing an effective medication is based on a trial
and error approach, there are some basic guidelines to rationale
treatment choice, including accounting for each patients other
comorbitidies and medications.18,25,26 The following are some of
the most commonly used preventives.
The beta-blockers metoprolol and propranolol have received a
level A recommendation, which means they have established
efficacy in 2 or more class I trials.27,28 They are the most widely
used class of medication for migraine prophylaxis. Propranolol
has been shown to be efficacious in a daily dose ranging from 40
to 240 mg/day.18 Metoprolol, timolol, atenolol, and nadolol are
also likely to be effective based on data from less rigorous trials.
Beta-blockers, especially the non-selective drugs, should be
avoided in patients with asthma or insulin-dependent diabetes
and should be used with caution in patients with risk factors for

944 | Headache | May 2014

heart failure or depression. Metoprolol may act as a substrate for

some of the ART medications and should be avoided in this
population.20,23 The most common side effects with beta-blockers
include fatigue, depression, nausea, dizziness, and insomnia.
These symptoms appear to be fairly well tolerated and seldom led
to premature withdrawal from trials.28
Anti-epileptic drugs (AEDs) also have proven benefit in headache prevention. Divalproex sodium and its analog sodium valproate are established as effective in migraine prevention
(multiple Class I studies).26 The most common side effects seen
with valproate are GI problems, including nausea and vomiting.
More serious adverse effects include thrombocytopenia, hepatitis,
and pancreatitis. Valproate should be avoided in women of childbearing age because of its risk of teratogenicity.25 It is commonly
used in combination with cART, with few known interactions. In
resource poor settings with high incidence of HIV, it is the drug
of choice for headache and epilepsy because of its low cost and
few interactions with ART.
The other widely used AED is topiramate, which was found to
have 50% reduction in monthly migraine frequency at daily
doses of 50-100 mg.27,28 Some of the common side effects include
paresthesias, fatigue, cognitive side effects, and anorexia. Rare but
more serious side effects are the development of kidney stones
and angle-closure glaucoma.17 There are no known listed interactions with cART.
The use of other anticonvulsants for the treatment of migraine
have been less well supported, including gabapentin and carbamazepine.27,28 Carbamazepine can induce the CYP450 system
causing lowered concentration of certain ART medications and
should generally be avoided in patients on ART.20
Antidepressants are the third category of medications with
proven efficacy for headache preventive therapy. The antidepressant class with the strongest evidence is the tricyclic antidepressants (TCAs), of which the tertiary amine amitriptyline has the
most data to support its use.27,28 It is commonly used as a preventive in HIV patients and can be helpful for other pain syndromes, including neuropathy. Anticholinergic side-effects are
relatively common with TCAs and appear to be more prominent
with tertiary than secondary amines.25,26
Nortriptyline, a secondary amine tricyclic, may be better tolerated and likely has similar efficacy. In a class I study, the
selective serotonin and norepinephrine reuptake inhibitor
(SNRI) venlafaxine (extended release 150 mg daily) significantly
reduced the number of headache days.26 The most common side
effects were vomiting and drowsiness. Selective serotonin
reuptake inhibitors are less effective than TCAs or SNRIs for
headache prevention outside the setting of depression.17,25
Although not uniform to the class, some antidepressant agents
such as fluoxetine can inhibit the CYP450 system, causing alterations in some of ART medications.20
While beta-blockers, anti-epileptics, and antidepressants are
considered first-line preventive treatment, other agents are com-

Headache Currents
monly used in certain situations. A guideline update found that
there are insufficient data for the efficacy of verapamil for
migraine prevention, although it is widely used in this setting and
validated for use in cluster headaches. Side effects include initial
increase in headache, and there can be a delay in effect of a few
weeks after initiating treatment. Verapamil is usually started at a
dose of 80 mg daily and is slowly titrated to effective doses,
usually in the range of 320-640 mg.25 Flunarizine, also a calciumchannel blocker, is sometimes used as a headache preventive,
although it is not available in the United States. Side effects that
can be seen with the calcium channel blockers include weight
gain, sedation, edema, and constipation.
Onabotulinumtoxin A (onabot) is approved by the US Food
and Drug Administration (FDA) for use in chronic migraine.
Onabot can be particularly useful in patients who have found
more conventional oral preventatives ineffective or intolerable.25
Some studies have demonstrated that NSAIDs can be efficacious
for migraine prevention. The NSAID most frequently used is
naproxen sodium, although there is similar data for indobufen,
mefenamic acid, and tolfenamic acid.18,19 However, chronic
NSAID use is limited by side effects and the potential for medication overuse headache. A more practical use of NSAIDs is
prophylactic treatment of pure menstrual migraine and
menstrual-related migraine.21 In both of these conditions, standing doses of an NSAIDs are used for 5 days around the beginning
of the menstrual cycle to blunt the intensity of the associated
headaches.19,21
Other less commonly used medications for headache treatment can have major interactions with ART and should be
chosen carefully. Zalcitabine and delavirdine should not be taken
at the same time as magnesium-containing medications, sometimes used as a migraine preventive.20
Paroxetine, sertraline, and diltiazem are rarely used in headache therapy but can act as inhibitors of the CYP450 system.
Haloperidol, sertraline, nifedipine, codeine, venlafaxine, and
some benzodiazepines can act as substrates, although they are
rarely used in headache therapy.23 Midazolam and triazolam are
contraindicated with PI or NNRTI therapy.20,23 Delavirdine may
cause serious adverse events if blood levels are elevated, which can
occur with concomitant use of midazolam, triazolam, and ergots.

CONCLUSION
Headaches are common in patients with HIV. While most are
due to primary headache syndromes, the etiology varies with the
level of immunocompromise, and clinicians must be vigilant
about excluding secondary causes such as intracranial opportunistic infections. MRI and CSF examination are essential in any
patient with advanced HIV and headache. Treatment should be
tailored to the individual context, including the frequency and
severity of the headache as well as comorbid HIV-related conditions and antiretroviral medications. For those with complicated

945 | Headache | May 2014

headache histories or refractory symptoms, referral to a specialized headache center is appropriate.

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