A 33-year-old woman presented at 10:30 pm to the emergency department with a generalized headache, distinctly different from her usual migraines, after a transient 2-hour episode at 3:00 pm of word-finding difficulty, right-sided facial weakness associated with paresthesia, and new-onset confusion.
The patient was normally fit and healthy and did not smoke cigarettes or drink alcohol. She had a history of Kallmann syndrome (hypogonadotropic hypogonadism with anosmia; see “Kallmann syndrome” sidebar below1–4) with a normal 46,XX female karyotype, secondary osteoporosis, and migraines with visual aura.
She was taking a combined oral contraceptive pill (drospirenone 3 mg, ethinylestradiol 30 μg) as hormone replacement therapy and propranolol for migraine prophylaxis.
Her maternal grandmother had an ischemic stroke in her 60s; there was no other personal or family history.
INITIAL EVALUATION
On admission, her oxygen saturation was 98% on room air, respiration rate 15 breaths per minute, blood pressure 160/78 mm Hg, heart rate 98 beats per minute, and temperature 36.6°C (97.9°F). She was alert and orientated to time, place, and person.
A full neurologic examination was entirely normal, with no signs pointing to the cranial nerves or upper or lower limbs. Her speech was fluent without any word-finding difficulties. A complete cardiovascular examination was normal with no audible murmur or carotid bruits, and she did not have any signs of systemic disease.
Laboratory tests at presentation, including a complete blood cell count, renal function tests, and blood glucose level, were normal. Electrocardiography showed normal sinus rhythm.
DIFFERENTIAL DIAGNOSIS
1. Which is the most likely cause of this patient’s symptoms?
Seizure
Hemiplegic migraine
Transient ischemic attack
Brain tumor
Stroke mimics are conditions that present with stroke-like symptoms.5
Seizure
Seizures are a common stroke mimic. In cases of unwitnessed seizure, the postictal state, which can feature limb paralysis (Todd paresis), speech disturbances, altered level of consciousness, and confusion, can be mistaken for an acute stroke.
Seizures are more common in patients who have previously had a stroke. Conversely, generalized seizures are sometimes an early sign of an acute stroke. However, a spectrum of diseases affecting the brain, including vascular, infective, malignant, inflammatory, developmental, and genetic conditions, can present with seizures.6
Most patients recover relatively rapidly from postictal symptoms, but in rare instances nonconvulsive status epilepticus can cause prolonged symptoms affecting speech and movement, which may make it hard to differentiate this condition from other diseases.5
KALLMANN SYNDROME
Kallmann syndrome is a rare genetic condition characterized by an embryologic defect in neuronal migration of gonadotropin-releasing hormone neurons.1 Patients present with classic features of congenital hypogonadotropic hypogonadism and anosmia (lack of sense of smell).
Kallmann syndrome is genetically heterogeneous and can result from sporadic or inherited mutations. Inherited forms can be transmitted in X-linked recessive, autosomal-recessive, autosomal-dominant with incomplete penetrance, and oligogenic modes of inheritance.2 The most common mutations are in the genes encoding anosmin-1 (ANOS1) and fibroblast growth factor receptor 1 (FGFR1).3 However, despite advances in molecular diagnostics, mutations are found in fewer than 30% of individuals with a clinical diagnosis of Kallmann syndrome, underscoring the complex and likely polygenic nature of the disease.3
Some patients have delayed puberty or growth, and many experience difficulties with fertility. Treatment includes lifelong hormone replacement therapy and management of associated complications such as infertility, osteoporosis, cardiac disease, and psychological disorders.4
Hemiplegic migraine
Migraine is another frequent stroke mimic. Symptoms can include aura with visual and sensory phenomena.7 Symptom onset is typically gradual and is traditionally described as a slow march through different vascular territories.5
Hemiplegic migraine is defined by temporary motor weakness that can mimic stroke and transient ischemic attack.8 It is rare, with a prevalence of approximately 1 in 10,000, and symptoms typically last for 48 to 72 hours.9 Basilar territory migraine is even less common, and its symptoms can include vertigo, slurred speech (dysarthria), ataxia, and reduced consciousness.8
If the diagnosis is in doubt, computed tomography or diffusion-weighted magnetic resonance imaging (MRI) can help; normal findings point to migraine rather than stroke or other conditions.10
Migraine symptoms can recur frequently, necessitating symptomatic treatment for headache and prophylactic therapy if recurrences are significant.
Transient ischemic attack
A transient ischemic attack is defined as neurologic dysfunction caused by focal ischemia in the brain, spinal cord, or retina without evidence of acute infarction.11
Current thinking on transient ischemic attacks focuses less on their transience and more on the ischemia—it is the absence of an ischemic lesion on neuroimaging that distinguishes transient ischemic attack from ischemic stroke. Even when symptoms persist for a prolonged period, some patients do not develop tissue infarction, and the episode is therefore classified as a transient ischemic attack rather than a stroke. Conversely, if imaging demonstrates infarction, the event is considered a stroke, even if clinical symptoms resolve rapidly.11
Brain tumor
The clinical presentation of brain tumors varies, depending on their location, size, and growth rate.12 Symptoms can include headache, seizures, focal neurologic deficits, cognitive changes, and symptoms of raised intracranial pressure.8 Tumors can also be detected incidentally without symptoms.
Low-grade gliomas sometimes initially present with focal seizures and symptoms that can mimic those of stroke or transient ischemic attack.5 On neuroimaging, these tumors can be mistaken for tissue infarction.13
SUBSEQUENT MANAGEMENT
The physicians in the emergency department decided that the patient had had a transient ischemic attack. At that time her ABCD2 score (based on age, blood pressure, clinical symptoms, duration of symptoms, and diabetes) was 4 of a possible 7, indicating a moderate risk of subsequent stroke. She was treated with aspirin and referred to the transient ischemic attack clinic. No brain imaging was obtained during her initial visit to the emergency department.
In the transient ischemic attack clinic a few days later, her physicians noted that her symptoms were different from her usual migraine. Also, she had a family history of stroke, although she had no personal risk factors for stroke or transient ischemic attack. Brain MRI was performed 10 days after her initial presentation and was reported as showing an established subacute-to-chronic infarct in the left frontal lobe (Figure 1).
Magnetic resonance image of the brain obtained 10 days after the patient’s initial presentation. Axial fluid-attenuated inversion recovery (FLAIR) fat-saturated sequence demonstrated a well-defined heterogeneous lesion with high signal intensity involving the left frontal lobe middle and inferior gyri with mild mass effect (arrow).
Further tests included a bubble echocardiogram, which showed a patent foramen ovale. Tests to rule out an underlying hypercoagulable state were negative. Bilateral carotid artery Doppler studies demonstrated normal anterograde flow bilaterally with no arterial abnormalities.
Her physicians decided she had had an ischemic stroke due to paradoxical embolism, and prescribed clopidogrel 75 mg daily. She subsequently underwent successful closure of the foramen ovale.
RISK FACTORS FOR STROKE
2. Which of the following is not a risk factor for stroke or transient ischemic attack?
Family history of stroke
Patent foramen ovale
Migraine with aura
Hormone replacement therapy in Kallmann syndrome
Family history of stroke
Family history of stroke, particularly involving parents, significantly increases personal stroke risk.14 This increased risk is thought to be due to an interplay of genetic predisposition, shared lifestyle factors, and inherited conditions such as hypertension or diabetes, which independently increase stroke risk.14
Patent foramen ovale
Paradoxical embolism, a rare cause of cryptogenic stroke, is the movement of a thrombus or mass through an intracardiac defect from the right side into the left-sided systemic circulation. Most of the time the defect is a patent foramen ovale, which results from failure of the foramen ovale to seal within the first year of life.15 Patent foramen ovale is very common, affecting around a quarter of the general population.
Although observational data have shown a higher prevalence of patent foramen ovale in patients with stroke, a causative relationship has yet to be established.15 However, mutations associated with prothrombotic states, namely the factor V Leiden and prothrombin G20210A mutations, are more prevalent in young patients with cryptogenic strokes with patent foramen ovale.14 Foramina larger than 2 mm have also been observed more often in cases of cryptogenic stroke, suggesting that their size may influence the likelihood of embolic events.16 These findings imply that certain features of a patent foramen ovale may independently contribute to stroke risk, even in the absence of identifiable venous thromboembolism.
Whether it is worthwhile to close a patent foramen ovale to prevent the recurrence of a paradoxical embolus has been disputed for the past 30 years, because up to now we have lacked convincing evidence that closure is more effective than medical therapy alone.17 However, the 2024 European Stroke Organisation guidelines18 support closure alongside antiplatelet therapy in patients age 18 through 60 years who have had a cryptogenic stroke with no other identifiable cause, citing strong evidence that closure prevents recurrence. Also, high-risk anatomic features such as an atrial septal aneurysm, a large right-to-left shunt, or a hypermobile interatrial septum have been associated with greater benefit from patent foramen ovale closure.19
Migraine with aura
Around a third of patients with migraine experience aura, which is thought to be due to a wave of activity spreading across the brain surface, known as a cortical spreading depression.20 The cortical spreading depression is thought to inhibit neuronal activity and is accompanied by changes in blood flow that result in migraine symptoms.21
Patients with migraine have about a 2-fold higher risk of cardiovascular disease and stroke.22 The strokes are most commonly small cortical diffusion-weighted imaging lesions rather than large territorial strokes.23 Interestingly, in a large twin study, migraine with aura was associated with a slightly higher stroke risk compared with absence of migraine (hazard ratio 1.27), but migraine without aura was not associated with increased risk.22 The mechanism underlying this increased risk is not clear, but it is hypothesized that unfavorable genetic and cardiovascular risk profiles may be responsible.22
Hormone replacement therapy in Kallmann syndrome
Women with Kallmann syndrome may need hormone replacement therapy. There is no evidence linking Kallmann syndrome to thromboembolic events.14 Clinicians should be aware that hormone replacement therapy in patients with congenital hypogonadotropic hypogonadism restores normal estrogen levels and is not prothrombotic.
Estrogen replacement in hypogonadotropic hypogonadism should be tailored based on age, the need for pubertal induction vs maintenance, and individual risk factors such as thrombotic risk profile, cardiovascular and metabolic health, and fertility wishes. Transdermal estrogen is preferred in many cases because it poses less thromboembolic risk. In addition, if the uterus is present, cyclic or continuous progesterone is required to prevent endometrial hyperplasia.24
Other stroke risk factors to consider in young women
Smoking in people younger than 55 was found in a meta-analysis to be associated with increased risk of stroke (relative risk 2.9).25 Autoimmune diseases and vasculitis are more common in premenopausal women and are hypercoagulable conditions.26 Other important stroke risk factors to consider in young patients include cervical artery dissection and noninflammatory arteriopathies such as fibromuscular dysplasia.
Pregnancy and its complications also pose unique stroke risks, which, though beyond the scope of this article, should be considered when a pregnant woman presents with acute neurologic symptoms.27
CASE CONTINUED: THE DIAGNOSIS RECONSIDERED
A year later, the patient was referred to the neurology clinic by her general practitioner because she was having more frequent word-finding difficulties and headaches, despite treatment. The neurologist believed that the symptom recurrence was concerning for an alternative diagnosis, and therefore asked a neuroradiology colleague to review the patient’s MRI results again (Figure 1).
3. What is the final diagnosis?
Cerebral infarction
Brain neoplasm
Cerebral abscess
Tumefactive demyelination
The patient’s brain MRI was consistent with a space-occupying lesion in the left frontal lobe with high T2 and fluid-attenuated inversion recovery (FLAIR) signal but no restricted diffusion. These findings indicate a low-grade primary brain neoplasm that had been misinterpreted as an infarct. A chronic infarct would demonstrate volume loss, not mass effect, and would demonstrate lower signal on the FLAIR sequence. Subacute infarctions demonstrate mass effect and restricted diffusion seen as high signal on diffusion-weighted imaging and low signal on apparent diffusion coefficient. The lesion also had rounded margins, atypical for infarction.
Neither the clinical presentation nor the imaging findings were consistent with broader differential diagnoses such as cerebral abscess, demyelination, or cerebritis. MRI with contrast was repeated (Figure 2).
The left frontal lesion (arrows) was still present and stable in size on repeat brain magnetic resonance imaging 1 year later. (A) Axial T2 sequence again demonstrated the heterogeneous high T2 signal of the lesion. (B) Axial T1 postcontrast sequence demonstrated areas of faint enhancement within the lesion. These findings were consistent with a probable glioma.
The neuro-oncology team thought that the neurologic symptoms represented seizures, which were successfully managed with lamotrigine. Thereafter, the patient underwent elective surgical resection of the brain tumor. Histologic analysis demonstrated an oligodendroglioma, grade 2 by the World Health Organization classification.
Kallmann syndrome is not known to have an association with primary brain neoplasms, including oligodendroglioma. However, a few case reports and mechanistic studies have postulated an association between genes involved in Kallmann syndrome and brain malignancy.28,29
OUTCOME AND FOLLOW-UP
The patient remains symptom-free with no evidence of tumor recurrence on surveillance imaging. She remains on hormone replacement therapy and continues to have annual follow-up by endocrinology and neuro-oncology teams.
TAKE-HOME POINTS
Accurate history-taking in young patients presenting with acute neurologic symptoms is vital to diagnose stroke mimics.
The clinical narrative influences the format and interpretation of subsequent imaging.
Differentiation of brain tumor from infarction can be aided by the presence of edema and absence of restricted diffusion on diffusion-weighted MRI.
Restoration of physiologic levels of estrogen with hormone replacement therapy in female patients with Kallmann syndrome does not increase their risk for thromboembolism.
DISCLOSURES
The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
- Copyright © 2026 The Cleveland Clinic Foundation. All Rights Reserved.
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