Episode 5: Pseudotumor Cerebri and Secondary Causes of Headache in Pregnancy

When is a headache more than just a headache? Amanda's headaches started with a twinge, but when she started to lose her vision, her doctors sent her to the ER. Were Amanda's doctors overreacting? Featuring expert interviews with obstetrical medicine specialist Dr. Niharika Mehta, neurosurgeon Dr. Petra Klinge, maternal fetal medicine specialist Dr. Erika Werner, and neurooncologist Dr. Alexander Mohler. Dr. Julie Roth hosts.

Key Takeaways:

• Secondary causes of headache warrant workup in pregnancy if a patient screens in with the "SNOOP" acronym - systemic/secondary, neurologic, onset, older, and prior headache history - or positional headaches.
• Neuroimaging modality should be based on how acute the symptoms are - CT is indicated for headaches less than 24 hours, stroke-like symptoms, or sudden onset first or worst headache of life; MRI/A/V without gadolinium is indicated for secondary headaches over 24 hours.
• Treatment of pseudotumor cerebri during pregnancy is indicated to relieve symptoms and to preserve the vision; visual loss is the major risk of this disorder.
• Labor and delivery methods in individuals with elevated intracranial pressure depends on the cause. In pseudotumor cerebri, if patients are symptomatic around the time of delivery, passive second stage (passive descent) with operative delivery should be considered as an alternative to caesarian section; Valsalva during vaginal delivery can increase the intracranial pressure.

Written Case: Pseudotumor Cerebri and Secondary Causes of Headache in Pregnancy

Dr. Niharika Mehta and Dr. Julie Roth

A 26 year old woman, currently pregnant at 29 weeks gestation, presents for evaluation of headaches. She had never had headaches before the pregnancy. Beginning in her second trimester, she began to have constant, throbbing, posterior head pain, worse in the morning and when lying down. She also developed floaters in her visual fields, particularly when changing position.

What concerns do you have in a pregnant patient with this headache pattern?

Headaches account for a third of all neurologic issues encountered in pregnancy. More than 80% of women in the reproductive age group experience headache at some point, making it a common occurrence in pregnancy[1]. While primary headaches (such as migraine, tension and cluster headaches, chronic daily headaches or medication overuse headaches) account for majority of the cases of headache seen in pregnancy, the presence of certain clinical features should prompt a thorough examination of possible differential diagnoses. The American Headache Society offers the mnemonic  SNOOP[2] to identify red flags in a headache history, that can help differentiate primary and secondary headaches:

-SYSTEMIC SYMPTOMS (fever, weight loss) or SECONDARY RISK FACTORS (HIV, systemic cancer);

- NEUROLOGIC SYMPTOMS or abnormal signs (confusion, impaired alertness or consciousness);

-ONSET: sudden, abrupt, or split-second;

- OLDER: new onset and progressive headache, especially in middle age >50 yr (giant cell arteritis); and

-PREVIOUS HEADACHE HISTORY: first headache or different (change in attack frequency, severity, or clinical features; and POSITIONAL component).

Applying the above mnemonic in this patient should prompt the clinician to consider secondary causes of headache (New onset, associated visual phenomena and positional component).

While the brain itself feels no pain, the pain-sensitive structures inside the head include the scalp, the skull, the blood vessels and the meninges. Any irritability or direct injury to one of these structures may result in headache pain. For example, headaches worse lying down or waking a patient from sleep at night can be due to elevated intracranial pressure. Sudden onset headaches, especially with neurological symptoms, can suggest rupture of a vascular anomaly such as aneurysm or arteriovenous malformation. And systemic symptoms, secondary risk factors, and older age can be risk factors for either inflammatory, infectious, or gradually expanding (such as neoplastic) lesions that irritate or damage these pain-sensitive structures over a longer period of time.

What is the differential diagnosis to consider in this patient presenting with suspected secondary headache in pregnancy?

When considering causes of headache in a pregnant woman, it helps to classify conditions into three categories: those that are specific to pregnancy; those that are exacerbated by or associated with pregnancy; and those that are unrelated to pregnancy.

Conditions specific to pregnancy include preeclampsia, a condition characterized by new onset of hypertension, proteinuria and multi-organ involvement, in the second half of pregnancy (after 20 weeks gestation). Patients with preeclampsia may progress to eclampsia (seizures) with subsequent development of PRES (posterior reversible encephalopathy syndrome) evident on MRI. Both preeclampsia and PRES present clinically with headaches.

Conditions exacerbated by or associated with pregnancy include arteriovenous malformations (AVMs) that might experience increased blood-flow and possibly increase in size due to pregnancy-related cardiovascular changes and blood volume expansion. Sinus headaches are also more frequently seen in pregnancy due to increased vascularity and mucus production, resulting in sinus congestion. In patients with pituitary adenomas, particularly macroadenomas, tumor growth can occur with pregnancy progression[3], and may present as headache. Pregnancy is a hypercoagulable state and although ischemic stroke is rare, cerebral vein thrombosis can be seen in pregnancy, particularly in the third trimester and postpartum period[4].

In pregnancy, an increase in intracranial pressure can result from increased intraabdominal pressure and subsequent reduced cerebral venous outflow, as well as hormonal effects with increased circulatory volume. Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, shows a predilection for young, obese women of childbearing age and although no definite association[5] has been found between pregnancy and IIH in case control studies[6], this condition is an important consideration in pregnant patients – especially as weight gain and increased circulatory volume are normal features of pregnancy.

Conditions unrelated to pregnancy include trauma, tumors, and infections, although it is important to consider listeria in the differential when treating meningitis in a pregnant patient.

Does this patient’s headaches warrant further evaluation? What sort of evaluation?

Yes. When it comes to headaches in pregnancy, the clinical history and examination – including vital signs, neurological exam, and funduscopic exam – are of utmost importance. A longstanding history of headaches, predictable semiology and normal exam findings would be reassuring factors. Any new-onset headache in pregnancy, and headaches accompanied by new neurological phenomena (visual, sensory, motor, or cognitive, for example), focal features on neurological exam, or abnormal fundoscopy would require neuroimaging. A physical examination of the patient should include a neurological exam to assess for abnormal motor or sensory findings (especially weakness or sensory loss in one or two limbs), gait instability, coordination difficulties (finger to nose test), or abnormal cranial nerve findings, most importantly: papilledema on funduscopic exam, abnormal visual fields, abnormal eye movements or pupillary responses, or facial asymmetry. Funduscopic exam can reveal retinal vasospasm or serous retinal detachment in cases of severe preeclampsia. Hyperreflexia is also noted in this condition and is a precursor of eclamptic seizures.

In pregnant patients with headache and associated neurologic features that have lasted over 24 hours, MRI (and possibly non-contrast MRA and MRV) should be considered. While gadolinium (MRI contrast agent) should be avoided in pregnancy whenever possible, the MRA and MRV do not require contrast. MRA can detect vascular malformations such as aneurysm and arteriovenous malformation. MRV dcan detect cerebral venous sinus thrombosis. A noncontrast MRI provides detailed imaging of the brain parenchyma and can detect causes of elevated intracranial pressure including cerebral edema (focal or diffuse) and hydrocephalus. Although gadolinium cannot be administered to pregnant patients, the lack of edema seen on the T2/FLAIR MRI images would argue strongly against a mass or tumor as the source of the pain. MRI is preferable to CT, both from a safety and sensitivity standpoint, but in an emergency (headache less than 24 hours, stroke-like symptoms, or sudden onset first or worst headache of life), CT is considered the standard of care. CT poses minimal radiation risk to the fetus. If fundoscopy is abnormal (papilledema, signaling raised intracranial pressure), neuroimaging should precede lumbar puncture.

The patient was found on physical exam to have bilateral papilledema but an otherwise unremarkable neurological exam, and was sent to the emergency room. She underwent a brain MRI, which was unremarkable.

What other testing is important at this point?

If neuroimaging is normal, lumbar puncture (LP) should be done for opening pressure and routine analysis. Routine labs include cell count and differential (to screen for infection), protein, glucose, gram stain and culture. A lumbar puncture can be safely performed in pregnancy in any gestation.

What is the most likely diagnosis? What other causes of headache should be explored?

The most likely cause of the headache in this patient is idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri. 

IIH presents with symptoms/signs attributed to increased intracranial pressure (e.g., headache, papilledema, transient visual obscurations or “dim-outs,” and pulsatile tinnitus). The incidence of IIH is 2 to 20 times higher in the primary risk group: overweight women of childbearing years. Its diagnosis in pregnancy is no different than outside of pregnancy; the characteristic findings are normal neuroimaging with elevated opening pressure on LP. Making the diagnosis is important to avoid permanent visual loss, which can occur in about 25% of IIH patients. Sending the patient for a visual field and dilated eye examination is crucial. Visual fields can be tracked over time to determine resolution or progression. About 2-12% of pregnancies are affected by IIH.[7]

Intracranial hypertension can sometimes be a secondary finding – in the case of cerebral venous sinus thrombosis, for example, elevated intracranial pressure can occur because of increased venous congestion, even without an associated venous infarct or hemorrhage in the vicinity. This finding might go unseen on a standard MRI, and therefore, MRV is recommended to image the cerebral venous sinuses. Outside of pregnancy, elevated intracranial pressure can also be caused by excess vitamin A (or vitamin A derivatives), antibiotics (tetracycline family, for example), steroids or hormone-based contraception, or underlying disorders like obstructive sleep apnea, endocrinopathies, infections (lyme disease, for example) and systemic lupus erythematosus (SLE).

The patient is diagnosed with idiopathic intracranial hypertension (IIH) based on imaging results. Lumbar puncture was encouraged, but the patient was too anxious to perform the testing, although it was offered on several occasions.

How is IIH treated? What are the risks of treatment in pregnancy?

Treatment is geared toward maintaining limited weight gain, low salt diet and diuretics—especially acetazolamide. Although the complete safety of acetazolamide during pregnancy is not known, therapeutic doses of acetazolamide during pregnancy are unlikely to pose a substantial teratogenic risk. Metabolic acidosis is a recognized complication of acetazolamide therapy in adults and transient neonatal metabolic acidosis has been reported in premature infants whose mothers were treated with acetazolamide[8]. Outside of pregnancy, topiramate and furosemide can be used to treat this condition; however, these drugs should be avoided in pregnancy whenever possible. If vision is threatened, frequent lumbar punctures can temporize while a more definitive procedure is arranged. Procedures used to treat this condition when medical therapy fails include: optic nerve sheath fenestration, venous stenting, or placement of a ventriculoperitoneal shunt. Optic nerve sheath fenestration is performed less commonly than the other two procedures, although all three can be effective. However, in pregnancy, these invasive procedures are usually avoided unless absolutely necessary – especially if the increased weight gain in pregnancy is felt to be the major player in the development of symptoms, because resolution after delivery may occur.

IIH is not associated with adverse pregnancy outcomes[9]. Delivery method should remain unaffected due to IIH, with obstetrical indications governing the decision to perform a cesarean section. However, where there is concern for visual loss, an assisted delivery with forceps or vacuum may be warranted to limit further increases in intracranial pressure with Valsalva/expulsion efforts.[10]

On acetazolamide, visual symptoms and headache completely resolved. Visual field testing was normal. Funduscopic exam in the office was normal. She underwent MRV, which showed mild narrowing of the transverse and sigmoid sinuses on both the right and left side. Thrombus was ruled out.

What are the implications of the MRV findings?

While the MRV in patients with IIH is often normal, the narrowing of sinuses on this patient’s MRV corroborate the diagnosis of IIH. The MRV definitively ruled out cerebral venous sinus thrombosis. Moreover, the narrowing of the sinuses is a finding – along with “empty sella” – that is often seen in IIH. It is unknown if congenitally narrow sinuses prevent venous outflow, leading to pressure buildup in the head – a process that might be exacerbated in states of increased total body fluid, like pregnancy – or if the pressure of the brain on the sinuses themselves is the cause of the narrowing. Outside of pregnancy, a patient with venous sinus narrowing and a lack of response to medical therapy might be a candidate for venous stenting, a procedure usually done endovascularly.

At 36 weeks gestation, the patient called to report that her symptoms had returned, including posterior headaches and floaters in her vision. She described her vision as “foggy” or as if she was looking through a smoky room. She also had periods in which she would temporarily lose her vision when she was bending over, blowing her nose, or during bowel movements. She had had no abnormalities on visual field testing throughout pregnancy to date.

What is the significance of these symptoms? What are the next steps?

In a situation in which the symptoms of elevated intracranial pressure return in a patient with high level of suspicion for IIH, the medication (acetazolamide) can be titrated to effect. Also, in this particular case, the diagnosis of IIH is assumed – in spite of no opening pressure on lumbar puncture to confirm. Therefore, lumbar puncture should again be offered – not only to measure the opening pressure, but also to remove some cerebrospinal fluid and hopefully reduce the symptoms. Repeating visual field testing can be useful for more constant visual symptoms, but episodic symptoms such as those described above can sometimes be missed.

The patient finally agreed to lumbar puncture in spite of extreme anxiety. She was given a dose of alprazolam, a benzodiazepine, in order to complete the procedure, which she ultimately tolerated well. She reported that her visual symptoms improved markedly after the lumbar puncture, but the headache remained – and in fact, worsened. Surprisingly, the opening pressure was normal (10 cmH20). Therefore, no cerebrospinal fluid was removed. After the lumbar puncture, her vision improved, but her headaches developed the opposite positional pattern – they were worse standing or sitting up and better lying down. She developed severe nausea when standing as well. Blood pressure was normal, and there was no proteinuria.

What are some other causes for intractable, severe headaches towards the end of pregnancy? And what is the implication of the “reverse positional” headache?

Preeclampsia and PRES were discussed previously, and should always be high on the list in a patient with suspected secondary causes of headache later in pregnancy. In this patient, normotension and the lack of proteinuria would argue against this diagnosis. She has already had neuroimaging, and so a new mass lesion or inflammatory or infectious lesion would be very unlikely. Aneurysm rupture would present suddenly, not gradually.

Finally, she has a new (reverse) positional feature to the headaches. They are better lying down than standing or sitting. Especially after lumbar puncture, these are the features of a spinal – or “low-pressure” – headache. In a patient who has not had a lumbar puncture, this “reverse positional” patter is also important to ascertain, because it can occur in a spontaneous low-pressure headache due to a dural leak. Treatment of low-pressure headaches – including a spinal headache – includes caffeine, aggressive fluid repletion (either oral or intravenous), and when conservative methods fail, another procedure known as a blood patch. A blood patch involves repeating the lumbar puncture – but with the intent of injecting some of the patient’s own blood into the subdural space, presumably to seal any leakage.

Are there labor and delivery implications? Can she push?

If there are clear signs of elevated intracranial pressure, pushing during vaginal delivery should be avoided. For example, in a patient with visual changes bending over or with Valsalva, pushing should be avoided to prevent a more permanent loss of vision. In this case, the patient’s headaches and visual symptoms worsened with Valsalva or bending over. Caesarian section can also contribute to fluctuations in blood pressure and therefore possibly to intracranial pressure. There is a third option – known as passive second stage with operative delivery, or passive descent. In this case, natural labor is planned but with the use of vacuum or forceps rather than pushing as the baby descends through the birth canal. This option minimizes or avoids “pushing” (Valsalva) while reducing the operative risks typically associated with caesarian section.

Anesthesiology goals should involve minimizing increases in intracranial pressure, primarily through pain reduction. Because patients with IIH do not have an obstructive process leading to a pressure differential between the cranial and spinal compartments, not only is dural puncture safe, but in symptomatic patients, it can be therapeutic.

Although a patient with spinal headache due to low intracranial pressure may be reluctant to pursue spinal anesthesia, there is no specific anesthesia risk in a patient with low pressure headaches. Blood patch can be administered as a treatment for this condition.

However, headaches remained severe in spite of treatment of the “spinal headache.” Vision impairment never returned, but due to severe headache pain and emotional distress, her baby was delivered at 38 weeks by caesarian section due to breach presentation. Following delivery, she had no signs of postpartum preeclampsia, and over 8 weeks, headaches gradually subsided.

Are there any additional tests she needs after delivery?

In this case, the etiology of the headaches remains a mystery. The papilledema and MRV findings support a diagnosis of IIH, and it is possible that the usual fluctuations of intracranial pressure, coupled with the timing of the acetazolamide she was taking and effects of the benzodiazepine she took prior to the lumbar puncture led to a falsely low opening pressure. Ideally, a repeat lumbar puncture would be useful to follow up on this finding, but the patient declined this test. Visual field testing should be repeated as a way to wean the patient off acetazolamide. Neuroimaging may be repeated to follow up on a finding such as narrowing of the venous sinuses, but it is not always necessary if symptoms resolve.

REFERENCES:

[1] Marcus DA, Scharff L, Turk D. Longitudinal prospective study of headache during pregnancy and postpartum. Headache 1999(39); 9:625-632

[2] Available at https://americanheadachesociety.org/wp-content/uploads/2016/07/Primary_OR_Secondary_ Headache.pdf. Last accessed on July 22,2017

[3] Molitch ME, Prolactinoma in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011;25(6):885

[4] Martinelli I. Cerebral vein thrombosis . Thromb Res. 2013 Jan;131 Suppl 1:S51-4.

[5] Thurtell MJ, Bruce BB, Newman NJ, Biousse V. An Update on Idiopathic Intracranial Hypertension. Rev Neurol Dis. 2010 Spring-Summer;7(2-3):e56-68

[6] Giuseffi V, Wall M, Siegel PZ, Rojas PB. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study. Neurology. 1991;41(2 ( Pt 1)):239

[7] Hopkins A, Alshaeri T, Akst SA, et al. Neurologic disease with pregnancy and considerations for the obstetric anaesthesiologist. Seminars in Perinatology 38 (2014) 359-369.

[8] Merlob P, Litwin A, Mor N: Possible association between acetazolamide administration during pregnancy and metabolic disorders in the newborn. Eur J Obstet Gynecol Reprod Biol. 1990 Apr;35(1):85-8

[9]Tang RA, Dorotheo EU, Schiffman JS, Bahrani HM. Medical and surgical management of idiopathic intracranial hypertension in pregnancy. Curr Neurol Neurosci Rep. 2004;4:398–409. 

[10] Bagga R, Jain V, Das CP, Gupta KR, Gopalan S, Malhotra S. Choice of therapy and mode of delivery in idiopathic intracranial hypertension during pregnancy. MedGenMed. 2005 Nov 10;7(4):42