RESIDENT & FELLOW SECTION Clinical Reasoning: A 54-Year-Old Woman With Progressive Headache and Neurologic Decline Yao Cheng, MD, and Joseph Zachariah, DO ® Neurology 2024;102:e209190. doi:10.1212/WNL.0000000000209190 Abstract Correspondence Dr. Cheng yaochengcy68@gmail.com MORE ONLINE A 54-year-old woman presented with headache and vasculopathy. She was treated for reversible cerebral vasoconstriction syndrome but continued to have clinicoradiographic decline with headache, seizures, systemic symptoms, and progression of vasculopathy on imaging. We present the diagnosis of a rare genetic disease with its various neurologic complications and systemic manifestations. Our case also illustrates the importance of differences in the metabolism of various antiseizure medications, recognition of which may avoid precipitating the disease. For multiple-choice questions relevant to Teaching NeuroImages and Teaching Video NeuroImages, find @greenjournal on X using the hashtag #NeurologyRF Section 1 Downloaded from https://www.neurology.org by Harvard University on 18 April 2024 A 54-year-old White woman with a medical history of migraine, anxiety, depression on duloxetine and buspirone, tobacco use, and prior polysubstance (cocaine and amphetamine) use presented to the hospital with a 3-month history of progressive headache. The headache was daily, 7–8/10 in severity, holocephalic, pounding, non-thunderclap, waxing and waning without triggers, with associated blurry vision, photophobia, phonophobia, nausea, and occasional vomiting. There were no alleviating factors including with position change. Outpatient magnesium oxide, buspirone, and butalbital-acetaminophen-caffeine were ineffective. She had a remote history of headache with similar characteristics. However, they were less severe. She had been sober from illicit drug use confirmed by urine toxicology screen. She continued to use marijuana and tobacco daily. On arrival, she was afebrile with blood pressure at 174/73 mm Hg. Basic laboratory results including prothrombin time were normal. She received migraine cocktails including prochlorperazine, diphenhydramine, magnesium sulfate, and ketorolac and was discharged home. She represented 2 days later and was found to have a right frontal cortical subarachnoid hemorrhage (SAH) on CT head (Figure, A). The CT angiogram (CTA) of the head and neck showed diffuse multifocal abrupt high-grade narrowing (Figure, B). She was not on blood thinners. Her neurologic examination was unremarkable. Questions for Consideration: 1. What is your differential diagnosis? 2. What other testing would you like to order? GO TO SECTION 2 From Corewell Health, Grand Rapids, MI. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. Copyright © 2024 American Academy of Neurology Copyright © 2024 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 1 Glossary ALA = aminolevulinic acid; ASM = antiseizure medication; CTA = CT angiogram; FLAIR = fluid-attenuated inversion recovery; PACNS = primary angiitis of the central nervous system; PRES = posterior reversible encephalopathy syndrome; RCVS = reversible cerebral vasoconstriction syndrome; SAH = subarachnoid hemorrhage. Section 2 Common etiologies of secondary headaches with convexity SAH include arterial vasospasm, dissection, aneurysms, vascular malformations, and cerebral venous sinus thrombosis. The location of convexity SAH and angiographic abnormalities of multifocal segmental narrowing raise concern for CNS vasculitis, reversible cerebral vasoconstriction syndrome (RCVS), and moyamoya disease. CNS vasculitis includes primary angiitis of the central nervous system (PACNS) and systemic vasculitic disorders, autoimmune diseases, or infection causing secondary CNS arteritis. PACNS requires prompt recognition and early treatment with immunosuppression.1 RCVS is considered noninflammatory and self-limited compared with CNS vasculitis. It has been associated with pregnancy, vasoactive agents, vasoactive tumors, hypercalcemia, unruptured aneurysms, and head trauma. Arteriopathy of moyamoya disease is characterized by bilateral stenosis affecting the distal internal carotid arteries with the presence of prominent collateral vessels, commonly seen in young people with Asian ancestry. Downloaded from https://www.neurology.org by Harvard University on 18 April 2024 The black blood MR vessel wall imaging protocol revealed concentric vessel wall enhancement of bilateral M2 segments (Figure, C). This protocol is used to detect pathologic changes within the vessel walls beyond the luminal abnormalities. By contrast, lumenography-based imaging modalities such as digital subtraction angiography or CTA are useful to analyze luminal stenosis or occlusion. 2 Studies have shown that distinct wall thickening with a smooth, uniform, concentric enhancement pattern is observed in vasculitis due to increased permeability of endothelium from inflammation causing contrast leakage into the arterial wall, whereas vessel walls in RCVS are typically nonenhancing or mildly enhancing, if present. 3 However, the utility of the protocol remains ambiguous because there are cases of RCVS with more than minimal wall enhancement. MRI brain showed right frontal SAH with corresponding punctate diffusion restriction and minimal adjacent fluidattenuated inversion recovery (FLAIR) changes. Lumbar puncture was obtained to exclude vasculitis secondary to connective tissue, autoimmune, or infectious etiologies and PACNS. CSF analysis was negative for evidence of CNS inflammation. The serum vasculitic work-up was unremarkable (Table). Question for Consideration: 1. How would you proceed to treat the patient? GO TO SECTION 3 2 Neurology | Volume 102, Number 5 | March 12, 2024 Neurology.org/N Copyright © 2024 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Figure Imaging Studies CT head showed right frontal cortical SAH (A). CTA head and neck showed diffuse multifocal abrupt high-grade narrowing (red arrows) (B). The black blood MR vessel wall imaging protocol revealed concentric vessel wall enhancement of bilateral M2 segments (white arrows) (C). Repeat MRI brain without contrast on day 9 of second admission showed progressive T2 and FLAIR changes in bilateral cerebral hemispheres with a superimposed new acute infarct (D, E). Repeat MRI brain with and without contrast on day 15 showed stable diffusion restriction and FLAIR signal changes. There is mild petechial microhemorrhage (F) associated with occipital diffusion restriction. Gradient echo sequence showed gyriform enhancement correlating with areas of FLAIR changes (G). FLAIR = fluid-attenuated inversion recovery; SAH = subarachnoid hemorrhage. Section 3 Downloaded from https://www.neurology.org by Harvard University on 18 April 2024 RCVS was believed to be the working diagnosis due to high clinical suspicion with an RCVS2 score of 5, unremarkable CSF studies, and unremarkable vasculitis work-up. Although the MR vessel wall imaging showed enhancement, recent studies have shown that vascular wall enhancement can be found in up to 50% of patients with RCVS.4 Patients with RCVS typically have normal CSF findings, whereas CSF studies in PACNS reveal inflammatory findings such as lymphomonocytic pleocytosis or protein elevation in more than 90% of patients.5 The patient was started on verapamil. Her home duloxetine and buspirone were discontinued because of concern for potentially increasing her risk of RCVS. Low dose divalproex acid 250 mg twice daily was started for seizure prophylaxis and mood stabilization. She was counseled on marijuana and tobacco cessation. After discharge, she developed abdominal pain and constipation. She presented to the ED multiple times because of headache and abdominal pain and was eventually readmitted 6 days after her prior discharge. Blood work was significant for elevated lipase and liver enzymes. She developed progressive systemic and neurologic symptoms including generalized tonic-clonic seizures, encephalopathy, vision loss, paraparesis, dysphonia, dysarthria, hyponatremia, tachycardia, hypertension, and respiratory distress necessitating ICU care. A repeat MRI brain revealed progressive T2 and FLAIR changes in the bilateral hemispheres with superimposed diffusion restriction reflecting progression of vasogenic edema and possible posterior reversible encephalopathy syndrome (PRES) (Figure, D–G). CTA showed progression of Neurology.org/N multifocal stenosis. Transcranial Dopplers showed progression of vasospasm (Table). Owing to clinicoradiographic decline despite removal of precipitating factors for RCVS, the diagnosis of primary CNS vasculitis was reconsidered. A 5-day pulse dose steroid course was initiated. A brain biopsy was obtained before the initiation of steroids and later returned negative for vasculitis. The secondary work-up of RCVS ruled out medications or drugs, hypercalcemia, pheochromocytoma, or carcinoid tumor as the cause (Table). Urine porphyrins were sent as part of the RCVS work-up especially with unexplained progressive neurovisceral symptoms, ultimately returned positive for porphyria. An 11day course of panhematin was initiated for acute hepatic porphyria. Her mental status and visual acuity improved rapidly. Her paraparesis improved over time but continued to have significant neuropathic pain. An EMG showed evidence of acute to subacute motor neuropathy (Table). Urine porphobilinogen (PBG) was elevated with normal urine deltaaminolevulinic acid (ALA). The diagnosis was later confirmed with genetic testing suggesting variegate porphyria. In retrospect, the family reported that the patient had darkcolored urine for months with a long-standing history of abdominal pain and photosensitivity before her headaches. The photosensitivity was intense enough for her to avoid the sun due to skin blistering. Discussion Porphyrias are a group of inherited disorders characterized by an enzyme deficiency in heme biosynthesis resulting in buildup of porphyrins causing systemic and neurologic symptoms. Most porphyrias are an autosomal dominant with Neurology | Volume 102, Number 5 | March 12, 2024 Copyright © 2024 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 3 Table Investigation Result Normal value Total calcium (mg/dL) 9.2 8.6–10.4 Prothrombin time (s) 10 9.7–12.6 ESR (mm/hr) 11 0–20 CRP (mg/dL) 0.3 0–0.5 Serum ANA, ANCA, antiphospholipid, anti-SSA/SSB, anti-smith, anti-RNP & anti-dsDNA Abs Negative Negative Hepatitis panel Negative Negative Coccidiodes Ab Negative Negative Histoplasma Ab Negative Negative CMV IgM and PCR Negative Negative HIV-1, HIV-2 Abs Negative Negative Cell count (/μL) 2 0–5 Protein (mg/dL) 38 15–45 Glucose (mg/dL) 67 40–70 CSF, AFB & fungal culture Negative Negative HSV-1, HSV-2, enterovirus, EBV, VZV, adenovirus, JCV & BKV-PCR Negative Negative West Nile IgM and IgG Negative Negative Lyme IgG Negative Negative VDRL Nonreactive Nonreactive Cryptococcus, Aspergillus, and Toxoplasma PCR Negative Negative Paraneoplastic panel Negative Negative VMA (mg/24 h) 3.3 0–7.9 5-HIAA (mg/24 h) 2.4 2.0–9.0 Toxicology screen Negative Negative Porphyrins Positive Negative Downloaded from https://www.neurology.org by Harvard University on 18 April 2024 CSF Urine TCDs Elevated mean velocities of both MCAs consistent with moderate vasospasm Brain biopsy Rare intraluminal fibrin thrombin without evidence of inflammation within the lumen EMG Widespread active denervation and chronic reinnervation not following a length dependent pattern. Sensory responses are relatively spared, consistent with a motor neuropathy incomplete penetrance, with a prevalence of approximately 0.5–10 per 100,000 people.6 Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria are the main subtypes causing neurologic diseases. Certain drugs, particularly medications with P450 metabolism, can precipitate porphyria attacks by stimulating heme production. In our case, the antiseizure medication (ASM) valproic acid may have aggravated an ongoing porphyria attack. 4 Neurology | Volume 102, Number 5 | March 12, 2024 Photosensitivity, dark urine, abdominal pain, and transaminitis are typical findings of porphyria. Hypertension and tachycardia are common because of activation of the sympathetic nervous system causing catecholamine release.7 The classic triad of neurologic manifestations includes motor-predominant peripheral neuropathy, neuropsychiatric disturbance, and abdominal pain. Typical neuropathy is an acute or subacute motor axonal neuropathy affecting mainly proximal muscles, generally worse Neurology.org/N Copyright © 2024 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. in the arms than the legs.8 Autonomic nerve dysfunction contributes to constipation and poorly localized abdominal pain.6 Seizures may be secondary to neurotoxicity or hyponatremia. Excess PBG and ALA induced SIADH through neurotoxigenic mechanisms might contribute to seizures in porphyria.7 PRES is by far the most common MRI abnormality in porphyria. Other MRI findings in reported literature include central pontine myelinosis, gyriform enhancement, and reversible splenial lesion syndrome.9 RCVS is rarely associated with porphyria, especially with the absence of typical thunderclap headache.10 A decreased production of the vascular dilator nitric oxide is believed to result in vasoconstriction.11 Downloaded from https://www.neurology.org by Harvard University on 18 April 2024 Diagnosing RCVS can be challenging because RCVS and CNS vasculitis frequently have overlapping features. Features such as thunderclap headache, vasoconstrictive triggers, female sex, and convexity subarachnoid hemorrhage were predictors of RCVS, which were incorporated into the RCVS2 score. Our patient’s presentation was also confounded by abnormal enhancement on vessel wall imaging. A rare RCVSPACNS overlap syndrome was hypothesized because intense, prolonged vasoconstriction may cause inflammation.12 As previously discussed, the utility of MR vessel wall imaging protocol remains ambiguous. Studies have shown that watershed infarcts and vasogenic edema are distinctive features for RCVS, whereas patients with PACNS have more diffuse distal artery involvement causing disseminated small infarcts and small vessel white matter changes.13 Previous studies showed comorbid RCVS and PRES at a rate of 15%–30%, signifying notable overlap between PRES and RCVS.14 PRES-like reversible cerebral edema can be seen in up to 38% of patients with RCVS.15 Nearly half of patients with PRES can have the angiographic sausage on a string pattern typically seen in RCVS.14 Removal of precipitating vasoactive substances, blood pressure control, rest, and empiric therapy with calcium channel blockers, such as nimodipine and verapamil, are associated with an excellent clinical outcome in RCVS. Medications such as sympathomimetics and serotonergic agents can cause hypertension and worsening of vasoconstriction. Study Funding The authors report no targeted funding. Disclosure The authors report no relevant disclosures. Go to Neurology. org/N for full disclosures. Publication History Received by Neurology July 6, 2023. Accepted in final form January 5, 2024. Submitted and externally peer reviewed. The handling editor was Resident & Fellow Section Deputy Editor Katherine Fu, MD. Appendix Authors Name Location Yao Cheng, MD Neurology, Drafting/revision of the manuscript for Corewell Health content, including medical writing for content; study concept or design; analysis or interpretation of data Joseph Zachariah, DO Neurology, Drafting/revision of the manuscript for Corewell Health content, including medical writing for content; study concept or design; analysis or interpretation of data References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. This case illustrates neurologic manifestations of porphyria such as motor neuropathy, RCVS, and seizures. Precipitants of porphyria including ASMs such as valproic acid, phenytoin, barbiturates, carbamazepine, and topiramate should be avoided. Rather, P450-sparing ASMs should be selected. Other neurologic medications with reported porphyrogenicity include benzodiazepines, estrogen, progesterone, certain anesthetics, and neuromuscular blocking agents. This case report also adds to a handful of cases worldwide associating porphyria with RCVS. Acknowledgment The authors thank Ronak Patel, DO, who contributed to collection of data and technical assistance. Neurology.org/N Contribution 11. 12. 13. 14. 15. de Boysson H, Parienti JJ, Mawet J, et al. Primary angiitis of the CNS and reversible cerebral vasoconstriction syndrome: a comparative study. Neurology. 2018;91(16): e1468-e1478. doi:10.1212/WNL.0000000000006367 Dieleman N, van der Kolk AG, Zwanenburg JJ, et al. Imaging intracranial vessel wall pathology with magnetic resonance imaging: current prospects and future directions. Circulation. 2014;130(2):192-201. doi:10.1161/ CIRCULATIONAHA.113.006919 Mandell DM, Mossa-Basha M, Qiao Y, et al. Intracranial vessel wall MRI: principles and expert consensus recommendations of the American Society of Neuroradiology. ANJR Am J Neuroradiol. 2017;38(2):218-229. doi:10.3174/ajnr.A4893 Chen CY, Chen SP, Fuh JL, et al. Vascular wall imaging in reversible cerebral vasoconstriction syndrome—a 3-T contrast-enhanced MRI study. J Headache Pain. 2018; 19(1):74. doi:10.1186/s10194-018-0906-7 Berlit P. Diagnosis and treatment of cerebral vasculitis. Ther Adv Neurol Disord. 2010; 3(1):29-42. doi:10.1177/1756285609347123 Tracy JA, Dyck PJ. Porphyria and its neurologic manifestations. Handb Clin Neurol. 2014;120:839-849. doi:10.1016/B978-0-7020-4087-0.00056-5 Spiritos Z, Salvador S, Mosquera D, Wilder J. Acute intermittent porphyria: current perspectives and case presentation. Ther Clin Risk Manag. 2019;15:1443-1451. doi: 10.2147/TCRM.S180161 Alqwaifly M, Bril V, Dodig D. Acute intermittent porphyria: a report of 3 cases with neuropathy. Case Rep Neurol. 2019;11(1):32-36. doi:10.1159/000496420 Yang J, Han F, Chen Q, et al. Reversible splenial lesion syndrome (RESLES) due to acute intermittent porphyria with a novel mutation in the hydroxymethylbilane synthase gene. Orphanet J Rare Dis. 2020;15(1):98. doi:10.1186/s13023-02001375-y Webb AJ, Ingale H, Irani SR, Hu MT. Acute variegate porphyria presenting with reversible cerebral vasoconstriction. Clin Neurol Neurosurg. 2016;146:102-104. doi: 10.1016/j.clineuro.2016.04.018 Takata T, Kume K, Kokudo Y, et al. Acute intermittent porphyria presenting with posterior reversible encephalopathy syndrome, accompanied by prolonged vasoconstriction. Intern Med. 2017;56(6):713-717. doi:10.2169/ internalmedicine.56.7654 Topcuoglu MA, Jha RM, George J, Frosch MP, Singhal AB. Hemorrhagic primary CNS angiitis and vasoconstrictive drug exposure. Neurol Clin Pract. 2017;7(1):26-34. doi:10.1212/CPJ.0000000000000324 Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol. 2016;79(6):882-894. doi:10.1002/ ana.24652 Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2008;29(3):447-455. doi:10.3174/ajnr.A0839 Pilato F, Distefano M, Calandrelli R. Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome: clinical and radiological considerations. Front Neurol. 2020;11:34. doi:10.3389/fneur.2020.00034 Neurology | Volume 102, Number 5 | March 12, 2024 Copyright © 2024 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 5