Stroke in Young Adults: Recognizing the Uncommon and Often-Missed Etiologies

Dr Neeraj Manikath , claude.ai

Abstract

Stroke in young adults (aged 18-50 years) presents unique diagnostic challenges, with approximately 10-15% of all strokes occurring in this age group. While traditional vascular risk factors account for some cases, a substantial proportion stems from atypical etiologies that are frequently overlooked in routine clinical practice. This review highlights commonly missed causes of stroke in young patients, offering practical diagnostic approaches and clinical pearls to enhance recognition and management. Understanding these hidden etiologies is crucial for appropriate secondary prevention and reducing recurrence risk.

Introduction

The incidence of stroke in young adults has paradoxically increased over recent decades despite advances in primary prevention, with rates rising by 44% in some populations between 1990 and 2010. While hypertension, diabetes, and dyslipidemia contribute to early-onset cerebrovascular disease, they explain only a fraction of cases. Studies suggest that up to 30-40% of young stroke patients have no identifiable traditional risk factors, and approximately 25% remain cryptogenic despite extensive investigation. This diagnostic gap often reflects inadequate consideration of age-appropriate differential diagnoses rather than truly unexplained pathophysiology.

The consequences of missed diagnoses extend beyond immediate morbidity. Young stroke survivors face decades of potential recurrence risk, and failure to identify specific etiologies may result in inappropriate or inadequate secondary prevention strategies. Furthermore, certain diagnoses carry genetic implications requiring family screening or have systemic manifestations necessitating multidisciplinary management.

Commonly Overlooked Causes

1. Cervical Artery Dissection: Beyond the Obvious Trauma

Cervical artery dissection accounts for 10-25% of strokes in young adults, yet remains underdiagnosed due to subtle or absent historical clues. While the classic presentation of neck pain or headache preceding focal neurological deficits is well-recognized, several clinical pearls warrant emphasis.

Pearl: Dissection can occur with trivial trauma or seemingly unrelated activities. Cases have been reported following yoga, hair salon visits with neck hyperextension, vigorous coughing, sneezing, or even prolonged laptop use with sustained neck rotation. The absence of significant trauma should never exclude dissection from consideration.

Oyster: Horner syndrome (ptosis, miosis, anhidrosis) occurs in approximately 50% of internal carotid dissections but may be incomplete or subtle. Specifically assess for dilation lag in the affected pupil using alternating light in dim conditions—the dissection-affected pupil dilates more slowly than its counterpart. Additionally, anhidrosis distribution distinguishes carotid (face and neck) from sympathetic chain lesions (entire hemibody).

Hack: In patients with posterior circulation symptoms and cervical pain, obtain vessel imaging extending to the skull base. Vertebral artery dissections are easily missed on routine neck imaging that terminates at C1-C2, as the V3 segment is most commonly affected. MRI with fat-saturated sequences demonstrating intramural hematoma remains the gold standard, but CT angiography showing irregular narrowing, intimal flap, or "string sign" is highly suggestive and more readily available.

Consider underlying arteriopathy in recurrent or bilateral dissections. Screen for fibromuscular dysplasia, vascular Ehlers-Danlos syndrome (type IV), Loeys-Dietz syndrome, and other connective tissue disorders through detailed family history, skin examination for translucency or easy bruising, and genetic testing when appropriate.

2. Patent Foramen Ovale and Paradoxical Embolism: The Devil in the Details

Patent foramen ovale (PFO) exists in 25-30% of the general population but is found in up to 50% of cryptogenic stroke patients under 55 years. However, PFO presence does not automatically establish causality, and distinguishing incidental from pathogenic PFOs remains challenging.

Pearl: High-risk PFO features suggesting causality include large shunt size (substantial right-to-left passage of agitated saline bubbles within three cardiac cycles), associated atrial septal aneurysm (excursion >10mm), prominent Eustachian valve directing flow toward the foramen, and Valsalva-provoking activity immediately preceding stroke onset.

Oyster: Always actively search for deep venous thrombosis (DVT) even in cryptogenic stroke with PFO. Perform bilateral lower extremity venous ultrasound and consider pelvic MR venography or CT venography, as isolated pelvic vein thrombosis may be the embolic source. A documented DVT substantially strengthens the case for PFO closure and may indicate underlying thrombophilia requiring anticoagulation rather than antiplatelet therapy alone.

Hack: In patients with cryptogenic stroke and suspected paradoxical embolism without identified PFO, consider pulmonary arteriovenous malformations (AVMs). These occur in approximately 30% of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) patients and can facilitate paradoxical embolism. Screen with pulse oximetry in upright and supine positions (orthodeoxia suggests pulmonary shunt), examine for telangiectasias on lips and oral mucosa, inquire about recurrent epistaxis, and consider transthoracic echocardiography with delayed appearance of agitated saline in the left heart (more than 3-5 cardiac cycles suggests pulmonary rather than cardiac shunt).

3. Antiphospholipid Syndrome: More Than Positive Antibodies

Antiphospholipid syndrome (APS) causes approximately 15-20% of strokes in young adults and represents the most common acquired thrombophilia. Despite established diagnostic criteria, APS frequently goes unrecognized due to testing errors and misinterpretation.

Pearl: APS can manifest as arterial or venous thrombosis, and the absence of prior venous thromboembolism does not exclude the diagnosis. Stroke may be the initial APS manifestation in up to 20% of cases. Multiple infarcts in different vascular territories, particularly involving both anterior and posterior circulation, should heighten suspicion.

Oyster: Laboratory diagnosis requires persistence of antibodies on two occasions at least 12 weeks apart. A single positive test is insufficient and may reflect transient positivity from infection or medications. Test for all three antiphospholipid antibodies: lupus anticoagulant (most specific), anticardiolipin antibodies (IgG and IgM), and anti-beta-2-glycoprotein-I antibodies (IgG and IgM). Lupus anticoagulant paradoxically prolongs phospholipid-dependent coagulation tests (aPTT, dilute Russell viper venom time) despite causing thrombosis, not bleeding.

Hack: Consider "seronegative APS" in patients with suggestive clinical features but negative standard antibody panels. Emerging evidence suggests that antibodies against phosphatidylserine-prothrombin complex, annexin A5, and domain I of beta-2-glycoprotein-I may identify additional patients. Furthermore, evaluate for underlying systemic lupus erythematosus (SLE) even in antibody-positive patients without overt rheumatological symptoms, as up to 40% of APS patients have or subsequently develop SLE. Screen with antinuclear antibody, anti-double-stranded DNA, complement levels, and complete blood count.

4. Fabry Disease: The Great Mimicker

Fabry disease, an X-linked lysosomal storage disorder from alpha-galactosidase A deficiency, causes 0.5-1% of strokes in young adults but up to 4% in selected populations with cryptogenic stroke. The diagnosis is frequently missed because classic manifestations may be absent or unrecognized.

Pearl: While the textbook presentation includes angiokeratomas, hypohidrosis, acroparesthesias, and corneal verticillata, many patients, particularly those with late-onset variants, present with isolated cardiac or cerebrovascular disease. Women with Fabry disease may have milder or atypical presentations due to X-inactivation patterns but remain at significant stroke risk.

Oyster: Inquire specifically about heat intolerance, decreased sweating since childhood, recurrent abdominal pain, proteinuria, and early-onset hearing loss. Examine carefully for angiokeratomas in the "bathing trunk" distribution, although these may be sparse or absent in atypical variants. Check for corneal verticillata on slit-lamp examination—present in virtually all hemizygous males and many heterozygous females.

Hack: Screen young stroke patients with white matter hyperintensities, particularly when involving the posterior circulation or pulvinar region of the thalamus, as this distribution pattern is characteristic. Check serum alpha-galactosidase A activity in males (virtually diagnostic if reduced) and proceed to GLA gene sequencing in females and males with borderline enzyme levels. Fabry diagnosis enables enzyme replacement therapy or chaperone therapy, potentially preventing progressive renal failure, cardiomyopathy, and recurrent stroke. Cascade family screening is essential given the hereditary nature.

5. Moyamoya Disease and Syndrome: Beyond Pediatric Neurology

Moyamoya disease causes progressive stenosis of the terminal internal carotid arteries and proximal Circle of Willis vessels with compensatory collateral vessel formation, creating the characteristic "puff of smoke" (moyamoya) angiographic appearance. While classically considered a pediatric condition, adult-onset moyamoya accounts for approximately 40% of cases and presents predominantly with ischemic stroke.

Pearl: Moyamoya should be considered in young Asian adults with stroke, particularly involving the anterior circulation or watershed territories. However, the condition occurs across all ethnicities. Bilateral involvement is characteristic of primary moyamoya disease, while unilateral cases may represent moyamoya syndrome secondary to underlying conditions including sickle cell disease, neurofibromatosis type 1, Down syndrome, previous cranial irradiation, or hyperthyroidism.

Oyster: Adults with moyamoya may present with hemorrhagic rather than ischemic stroke due to rupture of fragile collateral vessels, particularly in posterior circulation. Morning headaches or headaches precipitated by hyperventilation (crying, blowing up balloons) result from relative hypoperfusion and should prompt vascular imaging.

Hack: Standard stroke imaging may appear normal or show subtle watershed infarcts. The diagnosis requires dedicated vascular imaging with catheter angiography, CT angiography, or MR angiography demonstrating characteristic terminal ICA stenosis and lenticulostriate collaterals. Additionally, perform "ivy sign" assessment on FLAIR MRI—linear hyperintensities along cortical sulci representing slow flow through leptomeningeal collaterals. Screen for moyamoya in patients with recurrent strokes despite antiplatelet therapy, unexplained cognitive decline, or seizures in appropriate clinical contexts. Surgical revascularization (direct or indirect bypass) significantly reduces subsequent stroke risk.

6. Cervical Arteriopathies: FMD and Reversible Vasoconstriction Syndrome

Fibromuscular dysplasia (FMD) and reversible cerebral vasoconstriction syndrome (RCVS) represent distinct arteriopathies that disproportionately affect young women and frequently escape diagnosis.

Pearl: FMD affects medium-sized arteries, most commonly renal and cervical arteries. The classic "string of beads" appearance on angiography reflects alternating stenoses and dilations of the medial arterial layer. While asymptomatic FMD is common, dissection, aneurysm formation, and thromboembolism cause stroke. Screen for FMD in young patients with stroke and hypertension, particularly if refractory or early-onset. Bilateral carotid or vertebral involvement is characteristic.

Oyster: RCVS presents with recurrent thunderclap headaches (sudden-onset, severe headaches reaching peak intensity within one minute) over one to three weeks, with or without neurological deficits. Stroke results from severe vasoconstriction, potentially triggered by vasoactive substances (selective serotonin reuptake inhibitors, triptans, nasal decongestants, cannabis, cocaine), postpartum state, or sexual activity. RCVS is frequently misdiagnosed as primary angiitis of the CNS (PACNS), but CSF and brain biopsy are normal in RCVS.

Hack: Distinguish RCVS from PACNS and other vasculitides through temporal profile and imaging patterns. RCVS demonstrates multifocal segmental narrowing preferentially affecting proximal vessels that resolves within three months on repeat angiography. Cortical SAH or watershed infarcts are characteristic. Conversely, PACNS involves small distal vessels, causes persistent abnormalities, and typically presents with subacute progressive cognitive or neurological decline rather than thunderclap headache. Calcium channel blockers (nimodipine or verapamil) represent first-line RCVS therapy, while PACNS requires immunosuppression. Misdiagnosis may result in unnecessary and potentially harmful treatment.

7. Occult Malignancy and Hypercoagulability

Cancer-associated stroke accounts for approximately 5% of strokes in young adults but may be the presenting manifestation of occult malignancy. Multiple mechanisms contribute, including hypercoagulability, tumor embolism, disseminated intravascular coagulation, and treatment-related toxicity.

Pearl: Cryptogenic stroke, particularly when multiple or involving unusual territories, may herald malignancy. Adenocarcinomas, particularly of lung, pancreas, and gastrointestinal tract, most commonly associate with stroke through mucin-producing tumor cells activating coagulation. Hematological malignancies cause stroke through hyperviscosity, leukostasis, or thrombocytosis.

Oyster: Check D-dimer levels in young cryptogenic stroke patients. Markedly elevated D-dimer (>3-5 times upper limit of normal) without identified thrombosis suggests occult malignancy or alternative hypercoagulable state. Additionally, assess for microangiopathic hemolytic anemia and thrombocytopenia suggesting thrombotic microangiopathy from malignancy.

Hack: Age-appropriate malignancy screening is essential in cryptogenic stroke with elevated inflammatory markers, unexplained weight loss, or suggestive examination findings. This includes breast and cervical cancer screening in women and testicular examination in men, alongside CT chest/abdomen/pelvis in selected patients. Consider occult malignancy screening more broadly in patients over 50 years with cryptogenic stroke. Monitor for malignancy development over subsequent months to years, as stroke may precede cancer diagnosis by up to 12-24 months.

8. Mitochondrial Disorders: MELAS and Beyond

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) represents the most common mitochondrial disorder causing stroke, typically presenting between ages 5-40 years. The pathophysiology involves metabolic stroke from neuronal energy failure rather than vascular occlusion.

Pearl: MELAS strokes characteristically do not respect vascular territories, often involve posterior temporal-parietal regions, and may cause cortical laminar necrosis visible on FLAIR and diffusion-weighted imaging. Episodes are frequently triggered by metabolic stressors including infection, fasting, or exercise.

Oyster: Additional features include seizures (often the presenting manifestation), migraines with aura, sensorineural hearing loss, diabetes mellitus, short stature, and exercise intolerance. Maternal inheritance pattern is characteristic but paternal transmission can occur, and spontaneous mutations are common. White matter disease appears disproportionate to age and vascular risk factors.

Hack: Screen with fasting serum lactate and pyruvate, though normal levels do not exclude diagnosis. Muscle biopsy demonstrating ragged red fibers on Gomori trichrome stain confirms mitochondrial myopathy. Genetic testing identifies mutations in mitochondrial DNA, most commonly m.3243A>G in the MT-TL1 gene. Heteroplasmy (variable proportion of mutant mitochondrial DNA) explains phenotypic variability. Management focuses on supportive care, seizure control, and avoidance of valproate (worsens mitochondrial function) and statins (may exacerbate myopathy). L-arginine during acute events and for prophylaxis may reduce stroke-like episode frequency by improving nitric oxide-mediated vasodilation.

Diagnostic Approach

A systematic approach to young stroke includes three tiers of investigation. The first tier encompasses routine studies performed in all patients: brain MRI with diffusion-weighted imaging and MR angiography or CT angiography of head and neck, transthoracic echocardiography with bubble study, prolonged cardiac monitoring for atrial fibrillation, complete blood count, metabolic panel, lipid profile, hemoglobin A1c, and thrombophilia screening including antiphospholipid antibodies.

Second-tier investigations target specific etiologies based on clinical suspicion: transesophageal echocardiography for suspected cardiac source, vessel wall imaging for arteriopathy or vasculitis, lumbar puncture when infectious or inflammatory causes are considered, hypercoagulability panels including protein C, protein S, antithrombin, factor V Leiden, and prothrombin gene mutation, homocysteine level, and toxicology screening.

Third-tier studies address rare causes after standard evaluation proves unrevealing: alpha-galactosidase A activity and GLA sequencing for Fabry disease, NOTCH3 genetic testing for CADASIL when extensive white matter disease exists, homocysteine and metabolic screening for homocystinuria, mitochondrial genetics, serum and urine toxicology for drug screening, and age-appropriate malignancy screening. Consultation with vascular neurology, genetics, rheumatology, or hematology should be considered for complex or cryptogenic cases.

Conclusion

Stroke in young adults demands thorough evaluation extending beyond traditional vascular risk factors. Clinicians must maintain high suspicion for atypical etiologies, as these conditions often present with subtle clinical clues easily overlooked during routine assessment. Detailed history-taking regarding family history, systemic symptoms, and precipitating factors, combined with meticulous physical examination and strategic use of specialized testing, enables diagnosis of previously unrecognized conditions. Identifying specific etiologies permits targeted secondary prevention, potentially preventing recurrence and enabling treatment of underlying systemic disease. Furthermore, many conditions carry genetic implications requiring family counseling and screening. As the incidence of young stroke continues rising, internists and neurologists must remain vigilant for these commonly missed diagnoses, ultimately improving outcomes for this vulnerable population facing decades of stroke risk.

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