Veronica Hackenthal, MD

Women often experience perimenopausal changes in headache frequency, when migraines may worsen or new types of headaches begin. The following case series describes a possible 

 that appears to develop in overweight/obese women around the time of 

The case series concerns eight women who were seen by a single neurologist at the 

 over the course of one year. All the women described recent onset (within the last year) bilateral daily head pain. Pain was worse in the morning just before rising from bed, with reported intensity ranging up to 10/10. Only one out of the eight women described co-occurring migraine features. None were able to identify triggers.

The average age of onset was 57 years (two women were perimenopausal, the remainder were menopausal). Six out of the eight had a history of 

, which was either well controlled or in remission when the new headache symptoms started. Six out of the eight were either overweight or obese.

All patients had normal ophthalmic exams, with no evidence of disc edema. Trendelenburg in the 10 degree head-down tilt position precipitated immediate worsening of symptoms in all patients. MRI with or without contrast and MR venography were normal, except for small incidental venous anomalies in three patients. Lumbar puncture (LP) was performed on two patients and showed normal to low opening pressure. Both developed 

LP was not deemed curative. All women showed rapid response (within 2 to7 days) with near complete resolution of symptoms when treated with acetazolamide (7 patients) or spironolactone (one patient). All experienced headache recurrence when tapering off medication, and none were able to completely taper off medication.

The case series appears to identify a new subtype of chronic daily headache in overweight/obese women in their fifties and sixties. The Trendelenburg position, an indication of increased intracranial pressure, appears to be diagnostic. While the etiology remains unknown, it could be related to cerebrospinal fluid (CSF) pressure high enough above baseline to cause headaches, but not severe enough to cause disc edema.

Why these women developed increased CSF pressure is unknown but multiple causes may have worked together to cause the condition.

Increased BMI has been linked to elevated intracranial pressure. But weight alone may not be to blame, because not all women in this series were overweight or obese. Other contributing factors can include cerebral venous congestion, venous anomaly, and decreased estrogen levels causing cerebral venous insufficiency.

Other causes of increased CSF pressure were ruled out but include: intracranial mass lesions, venous thrombosis, vessel stenosis, jugular vein compression, decreased CSF absorption (eg, from past meningitis or intracranial hemorrhage), or increased CSF production (eg, from a choroid plexus lesion or malignant systemic hypertension).

• This case series describes a possible 

 of daily headache in middle-aged overweight or obese women
• Trendelenburg position appeared diagnostic, and indicated increased intracranial pressure
• All women responded well to CSF-pressure lowering medication
• The cause of increased CSF pressure was unknown; contributing factors could be increased BMI, hormonal factors, venous anomaly, and/or venous congestion

A new subtype of chronic daily headache presenting in older women

Articles

This case series appears to identify a new subtype of chronic daily headache in overweight/obese women in their fifties and sixties.

New Type of Chronic Daily Headache in Older Women?

People admitted to the hospital for migraine with aura have over two times 

 for later readmission for transient ischemic attack (TIA).

 Sometimes called “mini-stroke,” a TIA occurs when blood flow to the brain is briefly interrupted without causing permanent neurological damage. TIAs can increase the risk for later stroke.

 also found that people admitted with severe migraine that does not respond to medication (status migrainosus) may have almost five times increased risk of later readmission for subarachnoid hemorrhage (SAH), or bleeding into the space around the brain.

 that about 9% of cerebrovascular events are missed upon initial ED evaluation, and that over 80% of cases initially misdiagnosed as headache were actually SAH.

 That study highlighted how misdiagnosis can delay accurate diagnosis of SAH, an often fatal condition.

“Given the high likelihood of misdiagnosis of TIA and SAH, this should raise awareness for physicians evaluating aura-positive patients for TIA symptoms to avoid misclassification. In addition, physicians evaluating patients for status migrainosus may need to 

 and evaluate more often for a sentinel bleed of SAH,” wrote first author Lili Velickovic Ostojic, MD,

 of Mount Sinai Downtown, New York, and colleagues.

To get a better idea of the risk of later cerebrovascular events associated with a hospital admission for migraine, researchers accessed 2013 admissions data housed in the Nationwide Readmissions Database, which includes all payers and uninsured individuals in the US. They used ICD-9 codes to identify 12,448 adult migraine admissions, of which 80.1% were women with a mean age 45.56 years.

About 24% of included individuals had migraine with aura and 14% had status migrainosus. Then they evaluated readmission for acute ischemic stroke, TIA, SAH, and intracerebral hemorrhage 30, 60, and 90 days after the migraine admission. Results were adjusted for age and vascular risk factors.

• 30-day readmission rate per 100,000 migraine admissions:

• Migraine with aura significantly linked to two times increased risk for readmission for TIA (HR 2.13, p <0.01)

• Status migrainosus significantly linked to almost 5 times increased risk for readmission for SAH (HR 4.83, p=0.04)

The authors mentioned that the study can only reveal associations and cannot prove cause and effect. For example, based on these results it is unclear whether migraine with aura actually causes TIA, or whether migraine with aura is being misdiagnosed as TIA in some cases. They noted that more research is needed to clarify causality.

• Nationwide administrative claims-based study found admission for migraine with aura was linked over two times increased risk for later readmission for TIA

• Status migrainosus was linked to almost four times increased risk for SAH

• Results cannot prove causality, but may suggest misdiagnosis in some cases

1. Velickovic Ostojic L, Liang JW, Sheikh HU, Dhamoon MS. 

Impact of Aura and Status Migrainosus on Readmissions for Vascular Events After Migraine Admission

2. Tarnutzer AA, Lee SH, Robinson KA, et al. 

ED misdiagnosis of cerebrovascular events in the era of modern neuroimaging: A meta-analysis

Researchers sought to find whether the risk of later cerebrovascular events was associated with a hospital admission for migraine.

Migraine: Putting TIA and Acute Ischemic Stroke in Perspective

Studies have found that children who take antiepileptic drugs (AEDs) have lower bone mineral density and increased fracture risk, compared with those who do not take AEDs.

 of children with epilepsy treated with AEDS matched to twins, siblings, or cousins not on AEDs found increased prevalence of bone fractures and decreased bone volume in AED users.

Some researchers have postulated that impaired vitamin D synthesis related to AEDs may explain the association, but vitamin D status was not statistically significant between cases and controls in this study.

Impaired bone and muscle development in young people treated with antiepileptic drugs

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 (ART) during the earliest phase of HIV infection may not be enough to prevent formation of viral reservoirs and enable cure or long-term ART-free HIV remission, according to a case study of 2 patients 

 “HIV relapsed despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission,” wrote first author Timothy Henrich, MD, of University of California San Francisco, and colleagues.

One of the patients is the first documented case of an adult started on ART at one of the earliest opportunities after seroconversion. Other cases have been followed to see if some people can achieve functional “cure” for HIV. The Mississippi baby, a well-known example, tested positive for HIV at birth, was started on ART, and had undetectable HIV levels after a 5-month treatment interruption. Yet, at about age 4, HIV re-emerged. Other examples include 2 adult patients, one of which may harbor a genetic mutation associated with 

; the other underwent stem cell transplantation from a donor with a genetic mutation that prevents HIV entry into cells. In both patients, HIV levels have remained undetectable or extremely low off ART.

The problem with achieving cure or remission is the persistence of viral reservoirs in memory 

 in the blood or in tissues, which form a source of viral rebound upon ART discontinuation. To see whether very early initiation of ART can decrease viral reservoirs and prevent establishment of lifelong infection, doctors studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program at the University of California San Francisco. Both patients initially tested negative for HIV, were started on 2-drug PrEP regimens, and then converted to standard 4-drug ART regimens after confirmed HIV infection.

Patient A was a 54-year-old man who was started on ART 10 days after HIV seroconversion, with peak plasma HIV RNA of 220 copies/mL. Viremia was fully suppressed on ART, with no detectable HIV from the ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cells, and plasma.

As part of the study, Patient A underwent treatment interruption after 32 weeks of being on ART. After stopping therapy, he remained without viremia for 7.4 months, after which he rebounded with HIV RNA of 36 copies/mL. Within 6 days, his viral load increased to 59,805 copies/mL, and ART was re-started. Rebound plasma HIV sequences were the same as those during acute infection. Mathematical modeling revealed that the latent reservoir size in Patient A was about 200 cells before treatment interruption. Researchers estimated that about 1% of people with a similar HIV burden might be able to achieve lifelong ART-free remission.

Patient B was a 31-year-old man who was started on ART about 12 days after seroconversion, with peak plasma HIV RNA of 3343 copies/mL. No HIV was detected in tissue samples. However, low-level HIV RNA or DNA were intermittently found in his blood and CD4+ Tcells, and he did not undergo treatment interruption.

Experiments in mice showed that 1 out of 10 mice that received CD4+ cells from patient A developed very low level HIV viremia (201 copies/mL). Three out of 8 mice that received CD4+ cells from Patient B developed HIV viremia (1000, 5000, and 11,000 copies/mL).

The researchers hypothesized that if a true “curative window” of opportunity exists, it may be very small. For example, 

 who are started on ART within 2 days of receiving SIV infection can prevent infection, while those started 3 days after receiving SIV experience viral rebound after 

 Henrich and colleagues concluded “. . . , although HIV persisted indefinitely in both of these PrEP cases, a continuum may exist across PrEP, postexposure prophylaxis, and early ART strategies. Further investigation in larger cohorts of individuals treated extremely early following HIV infection is warranted.” A limitation of the study was the very small sample size because of the rarity of individuals who present with very early HIV infection.


• ART started at the earliest stage of acute HIV infection did not prevent formation of latent viral reservoirs, nor did it prevent HIV rebound upon treatment discontinuation
• Viremia was fully suppressed for 2 years in Patient A but rebounded 7.4 months after treatment discontinuation
• Low-levels of HIV RNA or DNA were intermittently found in Patient B’s blood and CD4+ Tcells, and he did not undergo treatment interruption
• Mathematical modeling suggests that the latent reservoir size in Patient A was about 200 cells before treatment interruption; it is surmised that about 1% of people with a similar HIV burden may be able to achieve lifelong ART-free remission
• Larger studies are needed to determine whether a “curative window” exists during which extremely early ART initiation can prevent lifelong infection

1. Henrich TJ, Hatano H, Bacon O, et al. 

HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: an observational study

. PLoS Med. 2017;14:e1002417.
2. Lifson JD, Piatak M Jr, Cline An, et al. 

Transient early post-inoculation anti-retroviral treatment facilitates controlled infection with sparing of CA4+ T cells in gut-associated lymphoid tissues in SIVmas239-infected rhesus macaques, but not resistance to rechallenge

. J Med Primatol. 2003;32:201-210.
3. Whitney JB, Hill AL, Barouch DH. 

Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys

Starting antiretroviral therapy during the earliest phase of HIV infection may not be enough to prevent formation of viral reservoirs and enable cure or long-term ART-free HIV remission.

Veronica Hackenthal, MD

Articles

New Type of Chronic Daily Headache in Older Women?

Migraine: Putting TIA and Acute Ischemic Stroke in Perspective

Mini Quiz: Antileptic Drugs in Children

Early Antiretroviral Therapy Initiation Does Not Lead to HIV Functional Cure