From Head to Toe

Katherine Keller, DO Internal Medicine Resident, Maine Medical Center

Maine ACP Annual Meeting Clinical Vignette- September 16, 2017

Initial presentation to PCP

● 28 year old healthy female presents with:

○ abdominal pain for 3 weeks

○ nausea/vomiting

○ notes hormonal intrauterine device removed and had medroxyprogesterone injection 1 week prior to symptoms

Emergency Room

● Presents to emergency room the next day with diffuse abdominal pain and burning pain in bilateral flanks

○ Abdominal CT normal besides questionable sludge in gallbladder

○ Noted to be hypertensive

○ Given ondansetron and analgesics

○ Started on hydrochlorothiazide for hypertension

Emergency Room #2:

● One week later brought to ED after being found confused and lethargic

● At this point patient is admitted

Past Medical History

Heterozygote for Factor V Leiden No personal history of venous thromboembolism

Medications

Hydrochlorothiazide

Medroxyprogesterone contraceptive injection

Family History

Factor V Leiden (Mother)

Deep venous thrombosis (Mother)

Social History

-Lives with her husband

-Works as a nurse

-Current everyday smoker

-Drinks alcohol occasionally

-Denies illicit drug use

Outside Hospital Course

Vital Signs: BP 170/132 HR 134 RR 9 T 36.7 SpO2 100% RA Labs: Na-125 K- 2.4 HCG- negative Physical Exam: Noted to have generalized tonic clonic seizure while in ED Non focal exam Cardiopulmonary within normal limits

Outside hospital Course

Admitted with encephalopathy and seizure EEG: Mildy slow background, no definite epileptiform activity CT head: Suspicious dense lesion in occipital lobe

Outside Hospital Course

Fig 1. MRI brain without contrast Bilateral cerebral watershed distribution subcortical edematous changes in occipital lobes

Outside Hospital Course

Assessment: ● Posterior Reversible Encephalopathy Syndrome (PRES)

Plan: ● Neurology consult ● Loaded with levetiracetam

● Started on oral antihypertensives

Outside Hospital Course

● Two days later develops right side visual field deficit

Outside Hospital Course

Fig 2. MRI brain without contrast Left occipital lobe infarction

……….Transfer to Maine Medical Center

http://dreamstop.com/wp-content/uploads/2016/09/ambulance-dream.jpg

What do we have on her problem list?

Problem list:

● Recent progestin contraceptive injection

● Abdominal Pain

● Seizure

● Posterior reversible encephalopathy syndrome (PRES)

● Ischemic Stroke

● Hypertension

Objective

Vital Signs: BP 123/ 83 P 99 T 36.9 RR 15 SpO2 98% BMI 21 Physical Exam: General: Somnolent and flat affect, delayed responses. HEENT: PERRLA, EOMI intact bilaterally. Moist mucosa. CV: Regular rate and rhythm. No murmur. Respiratory: Clear to auscultation bilaterally Abdomen: Soft, non tender, non distended Extremities: No lower extremity edema Skin: No rashes Neuro: CN: 2-12 intact, subtle right lateral visual field deficit Motor: Strength 5/5 throughout bilaterally Sensation: Intact throughout Tone: Normal

Objective

Labs:

138 104 8

3.9 20 0.57

16.3

13.7

202 7.3

99

Imaging

● Repeat MRI shows multiple cerebral watershed infarctions

● CTV head showed dural venous sinus thrombosis

Imaging

Fig. 3 MRI brain without contrast Multiple watershed zone cerebral infarctions

Imaging

Fig 4. CTA head and neck Diffuse narrowing of posterior and anterior cerebral arteries

Fig 5. CTA head and neck Normal

Imaging

Fig 6. CTA head and neck Diffuse narrowing of posterior and anterior cerebral arteries

Fig 7. CTA head and neck Normal

MMC Hospital Course

● Diffuse cerebral artery narrowing

○ Concern for reversible cerebral vasoconstriction syndrome (RCVS)

○ Cerebral angiogram with neurosurgery revealed diffuse vasospasm consistent with RCVS

○ Character of vessels did not appear to be consistent vasculitis

Why does this previously healthy 28 year old have reversible cerebral vasoconstriction syndrome?

What would you do next?

Reversible Cerebral Vasoconstriction Syndrome (RCVS)

Infectious disease:

HIV- negative

CSF studies- unremarkable

Vasculitides:

ANCA- negative

ESR- normal

CRP- normal

Autoimmune:

DS DNA -negative

ANA- negative

ESR- normal

CRP- normal

Medications/toxins:

Oral contraceptive pills

Triptans

Serotonergic antidepresseants

Marijuana

Cocaine

Problem list:

● Abdominal Pain

● Seizure ● Posterior reversible encephalopathy syndrome (PRES)

● Ischemic Stroke

● Hypertension

● Dural Venous Thrombosis

Problem list:

● Abdominal pain

● Seizure ● Posterior reversible encephalopathy syndrome (PRES)

● Ischemic stroke

● Hypertension

● Dural venous thrombosis

● Reversible cerebral vasoconstriction syndrome (RCVS)

Assessment and Plan

● Dural Venous Thrombosis

○ Secondary to hypercoagulable state and recent

progesterone injection

Assessment and Plan

● Dural Venous Thrombosis

○ Secondary to hypercoagulable state and recent

progesterone injection

● Ischemic stroke

○ Secondary to rapid blood pressure lowering in the

setting of “PRES” which was likely RCVS initially

Assessment and Plan

● Dural Venous Thrombosis

○ Secondary to hypercoagulable state and recent

progesterone injection

● Ischemic stroke

○ Secondary to rapid blood pressure lowering in the

setting of “PRES” which was likely RCVS initially

● PRES

○ Was this ever just PRES?

Assessment and Plan

● Dural Venous Thrombosis

○ Secondary to hypercoagulable state and recent

progesterone injection

● Ischemic stroke

○ Secondary to rapid blood pressure lowering in the

setting of “PRES” which was likely RCVS initially

● PRES

○ Was this ever just PRES?

● RCVS

○ Secondary to recent progesterone injection

○ All other work-up was negative

MMC Hospital Course

Treatment:

○ Calcium channel blocker, amlodipine, for vasospasm

○ Analgesics and gabapentin for headache

○ Dabigatran initiated for dural venous thrombosis

○ Discharged to inpatient rehab

What about the abdominal pain?

MMC Hospitalization #2

Patient returns 2 days after being discharge to inpatient rehab with Headache, abdominal pain, nausea, vomiting, and burning pain all over her body.

https://www.maryvancenc.com/wp-content/uploads/2009/10/period_pain.jpg

MMC Hospital Course #2

Fig 5. CTA head and neck Normal

Fig 7. CTA head and neck Normal

MMC Hospital Course #2

● Repeat inflammatory markers normal

● Patient continues to have “all over body pain” despite increasing gabapentin and oxycodone

● Writhes around in pain in her dimly lit room with very flat affect

● Questioned conversion disorder or situational anxiety disorder

Seizure

Peripheral Neuropathy

Abdominal Pain

Encephalopathy

What is going on?

MMC Hospital Course #2

Urine Porphobilinogen

349.5 (normal =< 1.3)

Acute Porphyria

Diagnosis:

Substantial elevations of urinary porphobilinogen, greater than 10, is sufficient for diagnosis of acute porphyria.

Treatment should be started immediately without waiting for additional testing.

Overview

Discussion: Acute Intermittent Porphyria

Katherine Keller, DO Internal Medicine Resident, Maine Medical Center

Maine ACP Annual Meeting Clinical Vignette- September 16, 2017

History Porphyrin and porphyria (identified in urine in 1871) are derived from the Greek word porphyrus, which mean purple.

Urine may be reddish in color due to the presence of excess porphyrins and the urine may darken after exposure to light.y

https://upload.wikimedia.org/wikipedia/commons/thumb/a/a8 /Urine_of_patient_with_porphyria.png/280px-Urine_of_patient_with_porphyria.png

Epidemiology

● Inherited, autosomal dominant gene but low penetrance

● Incidence 5 : 100,000

● More likely to manifest in women

● More common in individual of northern european descent

● Onset usually age 30-50

Pathophysiology ● Disorder in the production of heme due to faulty enzyme porphobilinogen deaminase

(PBGD)

● Mutations in porphobilinogen deaminase (PBGD) gene lead to reduced function

● Few with mutation will have symptomatic disease; many individuals with mutation in this gene will remain asymptomatic

Pathophysiology ● Accumulation of porphobilinogen in the cytoplasm

● Aminolevulinic acid synthase (ALAS) induction in liver leads to heme synthesis and activity of PBGD

● Metabolic stress, drugs, and restriction of carbohydrates lead to increases in ALAS

Clinical Manifestations

● Abdominal pain ● Peripheral neuropathy

○ Lower extremity pain ○ Paresthesias

● Central nervous system involvement ○ Seizure ○ Hypothalamic involvement can cause SIADH ○ MRI findings consistent with posterior reversible encephalopathy

syndrome (PRES) ○ Neuropsychiatric

● Neuropathic bladder dysfunction ● Red/dark urine

Exacerbating Factors

● alcohol

● tobacco

● change in sex hormones, mainly progesterone

● medications, antipsychotics and antiepileptics are main ones

● starvation

Encephalopathy and Acute Intermittent Porphyria

● Case reports of both PRES and RCVS have been seen in presentation of acute intermittent porphyria

○ Exact pathophysiology of each is not well known or studied

○ Clinically significant because the treatment of each is different

○ Rapid lowering of blood pressure can leading to infarction as seen in our patient

○ Prolonged vasoconstriction can cause ischemia in watershed areas as we saw in our patient

Treatment ● Our patient was treated with hemin which is standard

treatment of moderate to severe attack

Treatment ● Hemin reduces synthesis of ALAS which decreases accumulation of heme

precursors

● Carbohydrate loading is treatment option for mild attack

Questions?

Thank you: Dr. Stephen Hayes

Dr. John Paul Winters

Dr. Dave Sedar

Dr. Brian Perry

Dr. Mark Gorman

References: 1. Sood, Gagan MD, Anderson, Karl MD, Tirnauer, Jennifer MD. (2017) Pathogenesis, clinical manifestation, and diagnosis of acute

intermittent porphyria. Uptodate.

2. Grandchamp B, Beaumont C, deVerneuil H, et al. Genetic Expression of porphobilinogen deaminase and urod during the erythroid differentiation of mouse erythroleukemic cells. In: Porphyrins and porphyrias, Nordmann Y (Ed), John Libbey and company, London 1986. P. 35.

3. Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurence of acute attacks, precipitating factors, and associated disease. Medicine, Balitmore 1992. 71(1):1.

4. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyria: pathogenesis of neurological manifestations. Semin Liver Dis. 1998. 18(1):43.

5. Takata, Tadayuki & Kume, Kodai & Kokudo, Yohei & Ikeda, Kazuyo & Kamada, Masaki & Touge, Tetsuo & Deguchi, Kazushi & Masaki, Tsutomu. (2017). Acute Intermittent Porphyria Presenting with Posterior Reversible Encephalopathy Syndrome, Accompanied by Prolonged Vasoconstriction. Internal Medicine. 56. 713-717. 10.2169/internalmedicine.56.7654.

6. Soo Y, Singhal AB, Leung T, Yu S, Mak H, Hao Q, Leung H, Lam W, Wong LK. Reversible cerebral vasoconstriction syndrome with posterior leucoencephalopathy after oral contraceptive pills. Cephalgia. 2010; 30(1):42