Moya Moya disease and young hypertension

Journal club

1. Journal Club Subhatharshni Mohan Supervisor: Dr Loh Wei Chao

2. The Patient A CLINICAL SCENARIO

3. Name: Mr RH Age: 44 years Comorbids : Hypertension, T2DM Presentation: Recurrent TIA – left sided UL and LL weakness Headaches Episodes of vomiting

4. Physical examination: Unremarkable No abnormal neurological findings Investigations: Blood ix unremarkable ECG: SR, LVH strain pattern CT brain: no evidence of acute ICB/ focal brain parenchymal lesion

5. Adult Moyamoya Disease and Syndrome: Current Perspectives and Future Directions: A Scientific Statement From the American Heart Association/ American Stroke Association .

6. Introduction Adult moyamoya disease and syndrome are uncommon conditions with substantial morbidity and mortality L ack of consistent information for adult patients Various and persistent barriers

7. This scientific statement focuses on adult moyamoya disease and syndrome, providing updates on various aspects, including genetics, diagnosis, evaluation, natural history, and treatment

8. Methods Identification, acceptance, approval  10 writing group members I nitial meeting: June 21, 2022 7 sections: Definitions, Epidemiology, Genetics, Diagnosis and Evaluation, Medical Treatment, Surgical Treatment, and Future Research Directions 120 publications were selected English language PubMed and Cochrane Databases

9. DEFINITIONS

10. Moyamoya Disease Cerebrovascular steno-occlusive condition characterized by progressive stenosis of the terminal portion of the internal carotid artery and the formation of an abnormal network of dilated, fragile perforators at the base of the brain – ‘puff of smoke’

11. R emoves limitations of the previous definition no longer requires bilateral involvement of the intracranial carotid artery  proximal middle cerebral artery or anterior cerebral artery involvement suffices  unilateral disease is sufficient

12. Moyamoya Syndrome Diagnosed when a patient meets MMD criteria but has other comorbidities associated with the vasculopathy “Quasi Moyamoya ” RCMD Guidelines exclude atherosclerosis, hyperthyroidism, and head trauma  no universal agreement RCMD Guidelines also does not include sickle cell disease

13. Epidemiology Most epidemiological data come from Asia, where the disease is prevalent. In Japan Incidence : 0.35 to 0.94 per 100 000 person-years Prevalence: of 3.16 per 100 000 population

14. Epidemiology Kuriyama et al, Sato et al: w omen-to-men 1 .9:1; and 11% to 12% had family history Bimodal Age distribution: overall around 10 years and 40 years peak age of onset in men  10-14 years; women  20-24 years

15. Epidemiology In the US: incidence of 0.57 per 100 000 people/y Mean age at diagnosis: 32 years W omen-to-men  2.6:1 49% White, 24% Black,11% Asian, 11% Hispanic prevalence and incidence  Asian origin was highest Particularly Japanase  similar rates with Japanese studies

16. Epidemiology Recent studies  significantly increased in the US S ocioeconomic disparities, higher incidence low income urban living women patients 18 to 44 years of age Asian/Pacific Islanders

17. GENETICS Up to 12% MMD patients have a positive family history  indicating a strong genetic component The Ring Finger Protein 213 ( RNF213 ) is a susceptibility gene for MMD R4810K variant (rs112735431 resulting in Arg4810Lys): major founder variant for East Asians ( esp Japanese and Korean) non-R4810K variants: non–East Asian and certain Chinese populations Rare cases: mutations in the ACTA2 and GUCY1A3 genes

18. Modes of Inheritance and Penetration MMD is likely autosomal dominant with incomplete penetrance RNF213 R4810K variant shows low penetrance in heterozygotes but high penetrance in homozygotes Familial occurrence is higher in East Asian populations compared to White individuals

19. A pedigree analysis of highly aggregated Japanese families with MMD transmission is predominantly maternal affected mothers more often produce female offspring  epigenetic modification (genomic imprinting) 27   A recent population-based study in Korea on familial incidence and risk in 1 st degree relatives  highest in individuals with an affected twin, then sibling, mother, lowest when the relative was the father   F amilial occurrence in White individuals is rare

20. Genetic Screening Genetic testing may help differentiate MMD from other diseases in East Asian individuals, but its role in non-Asian populations is uncertain Incomplete penetrance of the disease even in those who test positive for one of the identified genes genetic testing may have no benefit in the general population limited benefit for unaffected members in familial cases with MMD

21. Genetic Screening Those with MMV and evidence of manifestations of a systemic disease should prompt further screening Achalasia  screened for  GUCY1A3 Down syndrome  Chromosamal analysis Noonan syndrome–like symptoms  TPN11  and  CBL  screening N eurofibromatosis  NF-1 gene testing.

22. Effects of Non-Genetic Factors Nongenetic factors are associated with MMD and MMS cranial radiation: rates of MMV 2% and 4.3% up to 60%, in patients with NF-1 undergoing radiation for optic nerve glioma autoimmune conditions I nfections: leptospirosis, HIV

23. DIAGNOSIS AND EVALUATION

24. Genetic Screening

25. Ischemia Involves anterior circulation  most commonly border zones Causes: hypoperfusion, thromboembolism, combined Hemorrhage intracranial or intraventricular patterns: pseudoaneurysms of the moyamoya collaterals Circle of Willis aneurysm formation and rupture  some present with SAH

26. Imaging Gold standard  Digital subtraction angiography RCMD  MRI and MRA in certain cases.

27. Suzuki Classification U sed to characterize the stage of the disease Based on changes observed over time in the angiographic intensification and decrease of moyamoya collaterals W idespread recognition but limited in practical application Relies on temporally serial evaluations

28. Recent emerging CT and MRI techniques assessment of brain tissue injury and leptomeningeal collateral recruitment (Ivy sign) 43   cost-efficient method for sequential follow-up Other Imaging Modalities

29. Heavy T2-weighted MRI  3-dimensional constructive interference in steady state can be useful to detect MMD-specific arterial shrinkage PET  measures oxygen extraction fraction  predict stroke in patients with carotid occlusion

30. MRI-based hemodynamic imaging assess the extent of autoregulatory exhaustion and hemodynamic impairment Not val idated in large prospective cohorts of MMD or MMS

31. NATURAL HISTORY

32. Data mostly from restrospective studies In the US, 5% year risk of recurrent ischemia 65% :unilateral disease 82%: bilateral involvement In Japan, recurrent hemorrhage occurs in ≈30% to 60% of patients over long-term follow-up

33. Korean cohort study of symptomatic MMD patients demonstrated 5- and 10-year stroke risks 15% and 40% in the hemorrhagic subgroup 17 % and 33% in the ischemic subgroup 4   Progression unilateral  bilateral disease ≈20% of patients ischemic or hemorrhagic symptoms in >50% of patients

34. MANAGEMENT

35. Mainstay of treatement is to reduce co-existing risks of stroke Antithrombotic use  controversial increased risk for hemorrhage lack of efficacy for prevention of hypoperfusion related ischemic events Antiplatelet use for prevention of ischemic vasculopathy may be reasonable Survival benefits greatest with Cilastazol Medical Treatment

36. Important aspect of medical management DM, HPT, Dyslipidemia Increased BMI and Homocysteine  higher risk of MMD Atorvastatin Use after surgical resvascularization  Improve collateral circulation shown to reduce frequency of migraine headaches Management of Additional Vascular Risk Factors

37. medications to avoid limit vasodilation  calcitonin gene-related peptide–targeted therapies enhance vasoconstriction  triptans, ergots lower blood pressure  β- blockers, calcium channel blockers Moyamoya Headache

38. Surgical treatments for MMD include direct (extracranial-intracranial anastomosis) Immediate revascularization technically demanding greater periprocedural complications  cerebral hyperperfusion syndrome indirect (apposition of extracranial tissues onto the brain surface) relies on angiogenic proliferation over days or weeks combined approaches Surgical Treatment

39. Intraoperative anesthetic management to reduce risk of intraoperative ischemic events normotension n ormocapnia Normovolemia CHS  prompt recognition and management Anesthetic & Perioperative Management

40. Endovascular treatment with stent or angioplasty is not advisable for ischemic moyamoya Hemorrhagic aneurysms of moyamoya vessels can be treated either endovascularly or with revascularization surgery Endovascular Management

41. CONCLUSIONS AND FUTURE RESEARCH DIRECTIONS

42. Challenges limited models for research absence of universally accepted diagnostic criteria small sample sizes need for proper outcome measurements

43. d eveloping high-quality global registries adopting unified language with clear definitions incorporating patient-centered outcome measures v alidation of appropriate surrogate markers of clinical significance utilising innovative methods to collect maximum, relevant data as efficiently as possible Recommendations

44. Back to The Clinical Scenario

45. Differentials for Young Stroke Hematologic Cardiac Arterial

46. Workup

47. REFERENCES Singhal, A. B., Biller, J., Elkind, M. S., Fullerton, H. J., Jauch , E. C., Kittner , S. J., … & Levine, S. R. (2013). Recognition and management of stroke in young adults and adolescents. Neurology, 81(12), 1089-1097. https://doi.org/10.1212/wnl.0b013e3182a4a451 Singhal, A. B., Biller, J., Elkind, M. S., Fullerton, H. J., Jauch , E. C., Kittner , S. J., … & Levine, S. R. (2013). Recognition and management of stroke in young adults and adolescents. Neurology, 81(12), 1089-1097. https://doi.org/10.1212/wnl.0b013e3182a4a451 Gonzalez, N. R., Amin- Hanjani , S., Bang, O. Y., Coffey, C., Du, R., Fierstra , J., … & Yaghi , S. (2023). Adult moyamoya disease and syndrome: current perspectives and future directions: a scientific statement from the american heart association/ american stroke association. Stroke, 54(10). https://doi.org/10.1161/str.0000000000000443

48. THANK YOU