Acute Postpartum Headache

Authors

  • Robert L. Glover MD,

    Corresponding author
    1. Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
    • Address all correspondence to R.L. Glover, Montefiore Medical Center, Department of Neurology, 111 East 210 St., Bronx, NY 10467, USA, email: rglover@montefiore.org

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  • Sarah Vollbracht MD,

    1. Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
    2. Montefiore Headache Center, Albert Einstein College of Medicine, Bronx, NY, USA
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  • Matthew S. Robbins MD

    1. Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
    2. Montefiore Headache Center, Albert Einstein College of Medicine, Bronx, NY, USA
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  • Conflict of Interest: The authors report no conflict of interest.

Presentation of Case – Robert L. Glover, MD, Adult Neurology Resident, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY

A 22-year-old woman 6 days postpartum originally presented to the emergency room in 2007 with headache. The patient underwent an elective cesarean section 6 days prior to presentation with use of epidural anesthesia after an uncomplicated pregnancy. Vaginal delivery was deferred because of her history of multiple previous cesarean sections. She began experiencing a bilateral frontal headache the day prior to arrival in the emergency room. She described the headache as 9/10 in intensity, of sudden onset, and with associated photophobia but no nausea or vomiting. Review of systems was otherwise negative. The patient reported no significant medical history and no history of headaches. She had undergone uncomplicated cesarean section deliveries in 2001, 2003, and 2005. She could not recall any family history of neurological symptoms or conditions, and denied the use of any alcohol, tobacco, or any illicit drugs.

Query by discussant Matthew S. Robbins, MD, Montefiore Headache Center, Albert Einstein College of Medicine, Bronx, NY: Were there any additional details offered regarding exacerbating or alleviating factors?

Response by Dr. Glover: Yes, the headache did not change with position or straining. Additionally, the patient did not feel nauseous or have any episodes of vomiting.

Her blood pressure and pulse were normal, and she was afebrile. Neurological examination was notable for diffuse hyperreflexia, including bilateral Hoffman's reflexes but no Babinski signs and otherwise demonstrated no neurological focality.

Query by discussant Matthew S. Robbins, MD: It was mentioned that the headache was sudden onset, were there any meningeal signs on examination?

Response by Dr. Glover: No, on examination the neck was supple.

She underwent computerized tomography (CT) scan of the head without intravenous contrast (Fig. 1). Multiple hypodensities in the frontal white matter were visualized. Based on imaging results, the patient was admitted to the neurology inpatient service. Results from human immunodeficiency virus testing, copper levels, antinuclear antibody, antineutrophil cytoplasmic antibody, as well as antibodies to Ro, La, and DNA, and were all negative or within normal limits. A comprehensive antiphospholipid battery was unremarkable. Rheumatoid factor was measured at 22.3 IU/mL (normal 0.0-20.0 IU/mL). Plasma fibrinogen level was 660 mg/dL (nl 185-450), erythrocte sedimentation rate (ESR) was 130 mm/hour (normal <21), and C-reactive protein was 1.0 mg/dL (normal <1.0). She underwent magnetic resonance imaging (MRI) (Fig. 2), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) studies of the brain. Although the MRA and MRV were unrevealing, the MRI demonstrated a hyperintensity on diffusion-weighted imaging sequences in the right part of the genu of the corpus callosum, with a corresponding hypointensity on apparent diffusion coefficient mapping, consistent with an acute infarct. Most notably, fluid-attenuated inversion recovery (FLAIR) sequences demonstrated a striking pattern of confluent hyperintensity in the temporal poles, as well as multiple regions of subcortical white matter hyperintensities scattered throughout both hemispheres.

Figure 1.

Computerized tomography scan of the head without intravenous contrast: multiple hypodensities seen in frontal white matter.

Figure 2.

Magnetic resonance imaging of the brain without contrast 2007. (A) Coronal fluid-attenuated inversion recovery sequence demonstrating multiple regions of subcortical white matter hyperintensities, including confluent areas in the temporal lobes. (B) Diffusion-weighted imaging demonstrating small area of restricted diffusion in the right genu of the corpus callosum. (C) Apparent diffusion coefficient with corresponding lesion.

Query by discussant Sarah Vollbracht, MD, Montefiore Headache Center, Albert Einstein College of Medicine, Bronx, NY: Was lumbar puncture performed and, if so, were there any notable results?

Response by Dr. Glover: Bedside lumbar puncture procedure was unsuccessful, and the patient was scheduled for an outpatient fluoroscopy-guided procedure. The patient was not placed on any medications, was discharged, and was lost to follow-up. She did not undergo a repeat lumbar puncture attempt.

Discussion of Differential Diagnosis of Postpartum Headache – Matthew S. Robbins, MD, Chief of Service, Neurology, Einstein Division, Montefiore Medical Center; Director of Inpatient Services, Montefiore Headache Center; Associate Program Director, Neurology Residency; Assistant Professor of Neurology, Albert Einstein College of Medicine, Bronx, NY

Neurological consultation for patients with acute postpartum headache in our experience is a common occurrence. The overall incidence of postpartum headache is high, with 1 large prospective study of 985 women revealing a 39% rate of headache in the first postpartum week.[1] The differential diagnosis of the acute, postpartum headache is broad. The puerperium (the weeks following childbirth) is a time of vulnerability to a variety of secondary and primary headache disorders mainly because of hormonal, physiological, procedural, and psychological factors (Table 1). The most common cause of postpartum headache in a recent series of 95 consecutive women was tension-type headache (39%), followed by pre-eclampsia/eclampsia (24%), post-dural puncture headache (16%), and migraine (11%).[2] Taken together, primary headache disorders accounted for nearly 50% of all postpartum headache cases.

Table 1. Factors Related to Provocation of Selected Secondary Headache in the Postpartum Period
FactorClinical Examples
Valsalva maneuver during labor
  • Aggravation of pre-existing space-occupying lesion
  • Expansion or rupture of a previously unruptured intracranial aneurysm
  • Cervical artery dissection
Hypercoagulability
  • Arterial stroke
  • Cerebral venous thrombosis
Epidural/spinal anesthesia
  • Post-dural puncture headache
  • Bacterial meningitis
Idiopathic but puerperium-specific
  • Pre-eclampsia and eclampsia
  • Reversible posterior leukoencephalopathy syndrome
  • Reversible cerebral vasoconstriction syndrome
Pituitary gland hypervascularity/expansion
  • Pituitary apoplexy
Intrapartum uterine hemorrhage
  • Sheehan syndrome

The patient previously described presented in the acute postpartum period with an abrupt onset, severe headache. She had clear “red flags”[3] that were strongly suggestive of the presence of secondary, or symptomatic, headache:

  1. She experienced new onset headache in the postpartum period.
  2. Her headache onset was sudden and seemed “thunderclap” – peaked to maximal intensity within 1 minute of onset.
  3. She possessed a clear change from a pre-existing headache pattern, namely an acute severe headache in a patient without any significant headache history.

This patient reported a thunderclap headache onset, which particularly mandates a thorough work-up of secondary causes and often signifies a secondary headache of a cerebrovascular origin. Had the CT scan been unrevealing, this patient would have likely been offered a lumbar puncture, mainly to rule out aneurysmal subarachnoid hemorrhage (SAH). When SAH occurs in association with pregnancy, it is much more likely to happen in the postpartum period, particularly within the first 2 postpartum weeks.[4] In the work-up of a thunderclap headache in most clinical contexts, the next step would be to proceed with more detailed neuroimaging, namely MRI of the brain, MRA of the head and neck, and MRV of the head, which usually would yield the diagnosis.[5]

Secondary Headache in the Postpartum Period

Acute headache in the puerperium mandates diagnostic vigilance for various secondary headache disorders. Table 2 denotes the most notable secondary headache disorders encountered in this population, and a few will be addressed in the context of this patient's presentation.

Table 2. Clinical Clues in the Differential Diagnosis of Secondary Headache Disorders Occurring in the Postpartum Period
Clinical ClueDiagnosis
Orthostatic headache patternPost-dural puncture headache
Relapsing thunderclap headachesReversible cerebral vasoconstriction syndrome
Single thunderclap headache

Aneurysmal subarachnoid hemorrhage

Reversible cerebral vasoconstriction syndrome

Cerebral venous thrombosis

Cervical artery dissection

Pituitary apoplexy

Hypertension

Pre-eclampsia/eclampsia

Reversible posterior leukoencephalopathy syndrome

Reversible cerebral vasoconstriction syndrome

Visual loss

Pre-eclampsia/eclampsia

Reversible posterior leukoencephalopathy syndrome

Pituitary apoplexy

Seizures

Eclampsia

Cerebral venous thrombosis

Reversible posterior leukoencephalopathy syndrome

Reversible cerebral vasoconstriction syndrome

Bacterial meningitis

Horner's syndromeCarotid artery dissection
Papilledema

Cerebral venous thrombosis

Idiopathic intracranial hypertension

Space occupying lesion (eg, neoplasm)

Bacterial meningitis

Focal neurological findings

Ischemic stroke

Intracranial hemorrhage

Cerebral venous thrombosis

Reversible posterior leukoencephalopathy syndrome

Reversible cerebral vasoconstriction syndrome

FeverBacterial meningitis

Pre-Eclampsia/Eclampsia

These disorders can present in the postpartum period, typically within 48 hours of delivery, although occasionally patients can present within 48 hours and 4 weeks of delivery, termed late postpartum pre-eclampsia/eclampsia. Patients typically present with a constant, throbbing headache that is usually bilateral and aggravated by physical activity.[6] Although these symptoms overlap markedly with migraine, it is the development of hypertension, peripheral edema, and for eclampsia, seizures, that indicate this diagnosis when headache is present. Abdominal pain, elevated transaminases, and thrombocytopenia may accompany more severe cases. A complicating factor is that migraine itself is a risk factor for the development of pre-eclampsia/eclampsia.[7] The patient presented earlier did not seem to have pre-eclampsia/eclampsia because of the lack of associated systemic findings, and the thunderclap headache presentation would be unusual unless there was an accompanying cerebrovascular disorder below.

Cerebral Venous Thrombosis (CVT)

Postpartum women are vulnerable to this disorder because of their underlying hypercoagulability. Acute headache, which can be thunderclap, is the most common symptom of CVT, but focal neurological deficits, seizures, and papilledema are often part of the clinical picture. Such a diagnosis was very plausible in this patient, and MRV imaging was warranted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

The peripartum period is an established risk factor for this condition, also referred to as posterior reversible encephalopathy syndrome, that may result from endothelial dysfunction and/or impaired cerebral autoregulation. In postpartum women, RPLS occurs either in the presence or in the absence of pre-eclampsia/eclampsia, and accordingly often features acute hypertension. Neurologically, patients typically present with headache that is usually generalized, but positive (including typical aura-like phenomena) and negative visual symptoms and varying degrees of altered mental status are also common. Seizures may also occur in more severe cases. A thunderclap headache presentation would be unusual unless it occurred in association with intracranial hemorrhage or reversible cerebral vasoconstriction syndrome (RCVS), which has been described.[8, 9]

RCVS

The puerperium is a major risk factor for this syndrome, and its presentation is distinctive for a pattern of relapsing thunderclap headaches in most patients, although occasionally, it can present with a single thunderclap headache,[10] which still places RCVS high on the differential diagnosis for this patient before neuroimaging. Exposure to vasoactive substances is another established risk factor, and RCVS may occur in the postpartum period particularly when epinephrine is used in epidural anesthesia for labor.[10] Other presenting symptoms may include transient or focal neurological findings and rarely seizures. Vascular neuroimaging reveals multifocal intracranial arterial vasoconstriction, although these abnormalities may only be seen several days after onset and be missed on an MRA performed shortly after headache onset.[10] RCVS may also be accompanied by RPLS, cervical artery dissection, and cortical SAH.

Other Causes of Ischemic and Hemorrhagic Stroke

Aside from CVT, RPLS, RCVS, and cervical artery dissection, the puerperium reflects a general period of hypercoagulability that places the postpartum woman at a higher risk of stroke than the general population, which includes cardioembolism.[11] The relative risk in the 6-week postpartum period is 8.7 (95% confidence interval 4.6-16.7) for ischemic stroke and 28.3 (95% confidence interval 13.0-61.4) for hemorrhagic stroke.[12] Hemorrhagic stroke would be more likely to present with headache, especially thunderclap headache, but the lack of focal neurological deficits renders would have rendered these diagnoses less likely. Nonetheless, other vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL),[13] are known to have a predilection for presenting in the peripartum period, and had the initial family history been available, this may have been higher on the differential diagnosis before neuroimaging.

Pituitary Apoplexy

Pituitary apoplexy is always in the differential diagnosis of thunderclap headache,[14] with particular relevance in pregnancy, where the pituitary gland may expand as much as 136% in size[15] because of an increase in lactotrophs, with an accompanying increase in vascularity.[16] The postpartum period usually reflects a period of time where the pituitary gland diminishes in size, but had the patient also presented with vomiting, altered mental status, visual or oculomotor deficits, or signs of pituitary insufficiency, it would have been a more likely diagnosis.

Post-Dural Puncture Headache (PDPH)

This condition is always a possibility when approaching the patient with acute headache in the postpartum period, especially when epidural anesthesia has been administered. The clinical hallmark of this condition is an orthostatic headache, which was lacking in this patient. Although thunderclap headache may occur at the onset of spontaneous intracranial hypotension, there is not a known association with PDPH.

Bacterial Meningitis

Bacterial meningitis seems rare in the postpartum period, but epidural and spinal anesthesia appears to be a major risk factor. The onset of headache, lethargy, and fever is usually within 24 hours of the administration of anesthesia and progresses rapidly, and severe cases may also feature seizures. Back pain may also be present because of the development of an infectious arachnoiditis. The organism involved may be from oral flora from the anesthetist (eg, Streptococcus salivarius) and can even occur in outbreaks. Group B Streptococcus meningitis is rare but may manifest even without the use of epidural or spinal anesthesia, and the route of systemic entry may relate to vaginal lacerations or an episiotomy.

Primary Headache in the Postpartum Period

Although pregnancy is largely protective for women who have migraine without aura, the postpartum period reflects a time of rapidly changing hormonal status and homeostasis, as well as sleep deprivation and psychological stress, and migraine may recur or even occur anew during this time. One large retrospective study of 1300 women with migraine addressing reproductive life events revealed that 4.5% of women experienced their first ever migraine attack during the 4-week postpartum period.[17] A prospective study revealed migraine recurrence rates of 34.0% by the end of the first postpartum week and 55.3% by the end of the first postpartum month.[18]

The influence of breastfeeding on the occurrence of postpartum headache remains unclear. The lactational amenorrhea induced by nursing is associated with a lack of cycling estrogen levels and as such would theoretically be protective against the occurrence of postpartum headache, particularly migraine. However, some18-20 but not all[21] studies verify this trend. Still, at our center, we typically counsel expectant mothers that aside from the well-established health benefits of breast-feeding, staving off postpartum migraine recurrence may occur as a result of nursing.

Patient Follow-Up – Robert L. Glover, MD, Adult Neurology Resident, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY

Approximately 6 years later, at 28 years of age, the patient again presented to the emergency room with headache. Much like her previous headache in 2007, the headache was bifrontal and of a pulsating quality.

Query by discussant Sarah Vollbracht, MD: Was the onset of the second headache sudden like the first attack?

Response by Dr. Glover: No, the second headache was not described as an acute onset like the first attack, and evolved gradually.

She could not recall any severe headaches since her first emergency department visit and reported no significant medical events between presentations. She had 1 additional child, born via cesarean section after an uneventful pregnancy, approximately 3 months prior to this presentation. Her neurological examination remained unremarkable. Complete blood count, basic metabolic panel, and coagulation studies were unremarkable. ESR was 25 mm/hour. Initial intravenous analgesic medications did not relieve the patient's symptoms, and urgent MRI studies were arranged from the emergency department (Fig. 3). Results were notable for high signal in temporal poles and the cerebral white matter on T2 sequences and multiple foci of high signal on FLAIR sequences. The patient's headache resolved shortly after treatment with intravenous metoclopramide and diphenhydramine, and she was discharged with neurological follow-up. At the initial outpatient office visit 2 months after her emergency room presentation, the patient remained headache-free. When pressed for family history, the patient stated that her mother had “white stuff in the brain,” suffered from frequent headaches, depression, and had recently been evaluated for cognitive decline. She also recalled that her maternal grandmother had suffered from dementia with onset after age 80. As her longitudinal clinical course and neuroimaging were suggestive of CADASIL, genetic testing for neurogenic locus notch homolog protein 3 (NOTCH3) gene was obtained. She tested positive for a deoxyribonucleic acid sequence alteration in the NOTCH3 gene located on the short arm of chromosome 19 that has been reported as a CADASIL-associated mutation.

Figure 3.

Magnetic resonance imaging of the brain without contrast 2012. (A) Coronal T2 sequence demonstrating high signal in temporal poles and the cerebral white matter. (B,C) Fluid-attenuated inversion recovery sequences with multiple foci of high signal.

Discussion of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) and Headache – Sarah Vollbracht, MD, Program Director, Headache Fellowship, Montefiore Headache Center; Assistant Professor of Neurology, Albert Einstein College of Medicine, Bronx, NY

CADASIL is the most common heritable cause of stroke and vascular dementia in adults, accounting for 2% of cases of lacunar stroke and leukoaraoisis in patients younger than 65 years and for 11.1% of cases in patients younger than 50 years.[22, 23] The overall prevalence is not well known. A small study from Scotland estimated that 4.14/100,000 cases were predicted mutation carriers and 1.98/100,000 cases have the definitive diagnosis.[24] Another small study from western England provided similar results, estimating the minimum prevalence of definite cases as 1.32/100,000, and the minimum prevalence of mutation carriers to be 4.10/100,000.[25] The prevalence may be higher, however, as sporadic cases have been reported.[26] Additionally, there is marked intrafamilial phenotypic variability, which may lead to under recognition of this disorder.[27]

Clinical Presentation

Although the clinical presentation of CADASIL can vary widely, it is characterized by 4 main symptoms: migraine with aura, subcortical ischemic events, mood disturbance, and cognitive impairment. The most frequent initial symptoms include migraine with aura and subcortical ischemic events. Symptom onset is typically in the fourth or fifth decade of life, but when the presenting symptom is migraine with aura, the age of onset is often younger, often in the third decade of life.27-29 There may be a gender difference in symptom expression in CADASIL patients, with migraine with aura being more prevalent in women and stroke being more prevalent in men younger than 51 years, a difference that seems to subsequently disappear in older patients. Age at first stroke, the number of stroke events, and the prevalence of dementia and psychiatric symptoms, however, does not seem to differ between men and women.[30] As exhibited by our patient, pregnancy and the puerperium appear to be a particularly vulnerable time for manifestation of neurological symptoms in CADASIL patients, and many patients may have their initial manifestation of CADASIL during this period.[31]

Migraine With Aura

The overall prevalence of migraine in all CADASIL studies has been calculated to be 38%, with a range of 5-72%, with lower prevalences reported in Asian countries and higher prevalences reported in Europe.[32] The vast majority of migraine sufferers with CADASIL, 80-90%, have migraine with aura.[27, 32] Rates of migraine without aura appear to be similar to the general population.[22] When migraine with aura is present, it is often the presenting symptom, and almost all migraine cases become symptomatic by age 38.[27] Aura characteristics are typical in 44% of cases, while 56% of cases also experience atypical features, including aura without headache, brainstem aura, hemiplegic aura, prolonged aura, or acute onset aura.[33] Severe attacks associated with fever, confusion, meningitis, or coma have also been reported.[34, 35] The frequency of attacks can be highly variable, and triggering factors are often typical for migraine headaches.[29]

Subcortical Ischemic Events

Subcortical ischemic events, whether transient ischemic events or completed infarctions, are the most frequent clinical manifestation of CADASIL, occurring in 65-85% of patients.27-29 The average incidence of stroke in CADASIL patients is 10.4 per 100 person-years.[36] The age of onset of ischemic events is usually in the fifth decade of life, and most patients have recurrent ischemic events. Two-thirds of strokes correspond to classic lacunar syndromes, with the remainder representing mostly small deep infarctions.[22] Large artery infarcts are usually absent, although large vessels may occasionally be involved in CADASIL.[37] Traditional vascular risk factors are usually not present, although hypertension, high cholesterol, and smoking have been reported in case series.27-29

Cognitive Impairment

Cognitive dysfunction is the second most frequent clinical manifestation of CADASIL, being reported in 40-60% of patients in some case series.[27, 28, 38] Cognitive dysfunction typically is slowly progressive, and patients demonstrate a stepwise deterioration, typical for vascular dementia.[27, 29] It is by nature subcortical, and many patients have frontal lobe features, such as disinhibition, perseveration, and apathy. Most develop gait disturbance, urinary urgency, and pseudobulbar palsy as the disease progresses.27-29 One of the earliest signs of cognitive dysfunction is impairment in executive function and processing speed, almost universally present by age 50 in 1 case series of 42 symptomatic patients. Frank dementia appears later in the course of the disease, with 75% of demented patients being older than 60 years.[39]

Mood Disturbance

Mood disturbances are present in 20-30% of patients with CADASIL and most frequently present as episodes of severe depression, although manic episodes have also been described. Mood disturbances are rarely the presenting feature of the disorder, often developing as the disease progresses.27-29 Apathy, perhaps as a manifestation of frontal lobe symptoms seen with the development of dementia in these patients, has been described in 41% of patients and can occur independently from depression.[40]

Other Clinical Manifestations

Other clinical manifestations of CADASIL are uncommon and perhaps coincidental or secondary to ischemic lesions and leukoencephalopathy. Seizures have been reported in 5-10% of patients, most of whom had a history of stroke and dementia.27-29,38 Intracerebral hemorrhages have been reported, mostly in hypertensive patients.[41, 42] Cerebral microbleeds, however, may be more common.[43] Parkinsonism, likely vascular, has been described.[44, 45] Rarely, hearing loss has been reported to occur.[46]

Neuroimaging Findings

With rare exception, MRI changes precede the development of clinical symptoms by 10-15 years and are almost universally present in all mutation carriers by the age of 35 years.[22] The most frequent MRI abnormalities are symmetric T2-weighted hyperintensities in the periventricular and deep white matter, involving the anterior temporal lobe, superior frontal lobe, external capsule, basal ganglia, thalamus, brainstem, and corpus callosum.29,33,47-49 Anterior temporal pole hyperintensities are perhaps the most specific MRI finding of CADASIL.[49] Also apparent on MRI are hypointensities on T1-weighted sequences corresponding to areas of lacunar infarctions and cerebral microbleeds apparent on gradient echo sequences.[43, 47]

Evaluation

When clinically suspected, molecular genetic testing and skin biopsy can be used to confirm the diagnosis as other tests, apart from the characteristic MRI findings described earlier, including cerebrospinal fluid composition, are usually normal in patients with CADASIL.[22, 50] While not specific for CADASIL, findings on ophthalmological examination can include nerve fiber loss, cotton wool spots, sheathed and narrowed arteries, tortuous arteries, arteriovenous nicking, and early macular and lens changes, although patients do not usually have ocular symptoms.51-53

CADASIL is an autosomal dominant disease caused by mutations in the NOTCH3 gene on chromosome 19. The NOTCH3 gene has 33 exons and encodes a transmembrane receptor with an extracellular domain containing 34 epidermal growth factor repeats (EGFRs). More than 150 mutations have been described, but all CADASIL-associated mutations occur in exons 2-24, which encode the 34 EGFR with most mutations occurring in exons 3 and 4. All described mutations lead to an odd number of cysteine residues within an EGFR. Genetic testing is the gold standard for diagnosing CADASIL and screening exons 2-24 has a 100% specificity and a sensitivity of nearly 100%.[22]

With the availability of genetic testing, skin biopsy is not routinely performed. It should be considered in patients with clinical, family history, and neuroimaging features suggestive of CADASIL who either do not have access to genetic testing, have a negative genetic test, or if genetic testing reveals a sequence variant of unknown significance. Skin biopsy reveals granular osmiophilic material within the basal membranes of vascular smooth muscle cells on electron microscopy.[54] Immunostaining with NOTCH3 monoclonal antibodies reveals accumulation of NOTCH3 protein in the blood vessel walls and has a sensitivity of 85-96% and specificity of 95-100%.[55, 56]

Treatment

There is no effective disease-specific treatment for CADASIL and current therapy addresses symptoms. For migraine with aura, conventional prophylactic medications are recommended if attack frequency warrants treatment. Acetazolamide has been anecdotally reported to be effective in the prophylaxis of migraine in CADASIL, but randomized, controlled trials are lacking.57-59 Acetazolamide has also been suggested to improve overall cerebral hemodynamics in CADASIL, perhaps suggesting a protective effect, but this has also not been proven in controlled trials.[60, 61] For acute treatment of migraine attacks, triptans and ergot derivatives should generally be avoided due to the high risk of stroke in these patients, and simple analgesics and non-steroidal anti-inflammatory drugs are preferred.[22]

For secondary stroke prevention, antiplatelet agents should be used over anticoagulants due to high prevalence of cerebral microbleeds, which may suggest an increased risk of symptomatic intracerebral hemorrhage.[43, 62] Cerebrovascular risk factors should be tightly controlled, including appropriate use of antihypertensive agents and statins.[22]

The efficacy of donepezil in the treatment of cognitive impairment in CADASIL patients was studied in a randomized, controlled trial of 168 patients. There was no significant difference between donepezil and placebo in the primary end-point, which was defined as a change from baseline in the score on the vascular Alzheimer's disease assessment scale cognitive subscale at 18 weeks. Improvement was noted, however, on several secondary end-points that were measures of executive function, but its clinical significance remains unclear.[63]

An important aspect of care in CADASIL patients is supportive and involves rehabilitation, physiotherapy, psychiatric and psychological support, and nursing care. Genetic counseling is also important for these patients and for their at risk asymptomatic family members.[22]

Summary of Case and Learning Points – Morris Levin, MD, Section Editor

Acute head pain in the postpartum period should raise concern, especially if “red flags” are present, as Dr. Robbins points out. The differential diagnosis of sudden severe headache is long, and even when diagnostic testing is negative, a high suspicion level should persist before diagnosing sudden acute (“crash”) migraine or benign thunderclap headache. In this case, initial work-up might have yielded the diagnosis of CADASIL, but the patient was lost to follow-up and further evaluation was halted.

It is peculiar that this genetic disease produces in most patients characteristic migraine auras and headaches. Is a migraine genotype linked genetically to the defect of CADASIL? Does the pathological process in CADASIL lower the threshold for cortical spreading depression or trigemnovascular activation? And do the migraine-like headaches lead to strokes? If so, is this similar to the etiopathology of “migraine stroke?” To make things more interesting, there are several other genetic diseases in which migraine headaches are part of the phenotype: retinal vasculopathy with cerebral leukodystrophy; hereditary infantile hemiparesis, and retinal arteriolar hypertortuosity and leukoencephalopathy.

Certainly, most patients with CADASIL ultimately present with far more than migraines with aura – significant behavioral abnormalities and strokes in addition to the severe headaches. There is no effective disease-altering treatment at present, as was pointed out by Dr. Vollbracht. To make matters worse, triptan and ergot derivatives are contraindicated. Recently, it has been suggested that Friedrich Nietsche who developed headaches and severe mental illness suffered from CADASIL, as opposed to syphilis as was previously supposed (Hemelsoet D, Hemelsoet K, Devreese D. The neurological illness of Friedrich Nietzsche. Acta Neurol Belg 2008;108:9-16).

As a point of interest, white matter lesions (WMLs) and headaches can be seen in other settings including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), cerebral vasculitis (either primary or as part of a systemic vasculitis), and multiple sclerosis. There are differences however in the location and appearance of the WMLs. The WMLs of CADASIL are symmetrical and confluent, and are best seen on FLAIR and T2 MRI sequences. Small ischemic lesions are the norm, with the appearance of lacunes. The WMLs in MELAS and in cerebral vasculitides are more assymetrical and involve both gray and white matter. In MELAS, WMLs tend to be clustered in frontal and anterior temporal regions. WMLs in MS frequently involve the corpus callosum, brainstem, and cerebellum, and they often have an ovoid shape with orientation perpendicular to the lateral ventricles (Dawson's Fingers).

Self-Assessment Questions

  1. What are “red flags” (ie, reasons to pursue a more thorough work up) for headaches in the postpartum period?
  2. What constitutes a thorough work-up of a suspicious postpartum headache?
  3. How can you distinguish between SAH and RCVS when there is SAH seen on CT or MRI?
  4. How do the ischemic changes seen in CADASIL differ from more common cerebrovascular ischemic disease?
  5. Draw a typical genogram for a family with CADASIL.
  6. Draw a typical genogram for a family with MELAS.

This case presentation and discussion address the following areas of competency in post-graduate medical education: patient care, medical knowledge, practice-based learning and improvement, communication skills, and systems-based practice.