Ng FL, Lobo MD Department of Clinical Pharmacology The William Harvey Research Institute Barts and The London School of

1. Complex Labile Hypertension: A Life On Hold Ng FL, Lobo MD Department of Clinical Pharmacology The William Harvey Research Institute Barts and The London School of Medicine BHS Annual Scientific Meeting 14th September 2011

2. Referral from University Hospital Galway • Mr JK, 48 year old male, Construction Worker • Frequent paroxysms of flushing • Uncontrolled hypertension for 14 months • Minute-to-minute lability on intra-arterial monitoring • Surges on standing, activity and alerting factors • Collapses postulated secondary to hypotension

3. Admission to Royal London • Worsening symptoms over preceding two years • Flushing, sweating with nausea • Palpitations • Paraesthesia of fingertips • Severe headaches • Early morning epistaxis • Collapses • Erectile dysfunction • Nocturia • Sensations of heat in the body • Lethargy

4. Additional history • Other Past Medical History • Pneumonia aged 33 • Current Medications • Clonidine 450 micrograms tds • Prazosin 1mg bd • Metoprolol 75mg tds • No drug intolerances • Ex-smoker • Nil EtOH since on medications • No recreational drugs or over the counter medications

5. Examination • BMI 28.4 kg/m2 • Absent left radial pulse with previous arterial line • Otherwise unremarkable

6. Initial management plan • Initially withhold medication • Bed rest and non-invasive monitoring • Specialist investigations: • Autonomic testing • Autoimmune profile and anti-neuronal auto-antibodies • Urinary metanephrines and plasma catecholamines • MRI brainstem • Whole body PET FDG Scan

9. Autonomic Testing

10. Autoimmune profile • ANA Positive 1/640, speckled pattern Anti-Scl-70 Positive • Anti-Jo-1 Negative Anti-RNP Negative Anti-Sm Negative Anti-Ro Weak positive Anti-La Negative Anti-ds DNA Negative • Anti-neuronal antibodies Negative

11. Further investigations • Clinical Neurophysiology • No abnormalities • MRI Brainstem • No evidence of brainstem abnormalities • Positron Emission Tomography • No evidence of malignancies • Skin punch biopsy histology • No evidence of small fibre neuropathy

12. Summary • 48 year old gentleman with • Progressive symptoms associated with paroxysmal hypertension, symptomatic hypotension and autonomic dysfunction • Testing confirming widespread autonomic dysfunction • Autoimmune profile suggestive of scleroderma/UCTD • Diagnoses • Extreme blood pressure lability due to dysautonomia • Autoimmune small fibre neuropathy secondary to underlying scleroderma/UCTD

13. Management • BP control and stability achieved through strict bedrest • Diazepam was initiated to attenuate alerting responses • Methyldopa and clonidine patches improved symptoms • Discharged with: • Clonidine patch 100 micrograms/day • Methyldopa 1g at 08:00, 1g at 16:00, 500mg at 20:00 • Diazepam 5mg at 09:00, 5mg at14:00, 3mg at 22:00

15. Commentary...

16. Results of autonomic testing... • Parasympathetic function reduced • Generalised failure of Sympathetic function to deep and cutaneous targets • Denervation Hypersensitivity to phenylephrine • Poor BP stability during orthostasis (SBP varied by 112 mm Hg) • However: normal resting supine BP (MAP 92.4 mm Hg) and normal muscle sympathetic tone during isometric exercise

17. What do the tests mean? • The patient is not hypertensive per se but has very poor BP stability • The responsible neurons are small, thinly myelinated or unmyelinated fibres • No evidence of large fibre peripheral neuropathy

19. Further plans • Repeat skin punch biopsy of Left leg • Thermal Threshold testing • Nail fold capillaroscopy • Rheumatology review • Adjustment of antihypertensive medications to better control BP surges • Consideration of IV γ-globulin therapy to arrest immune-mediated neuropathy