Fatal reversible cerebral vasoconstriction syndrome

Accepted Manuscript Fatal reversible cerebral vasoconstriction syndrome

Amy Kunchok, Helen C. Castley, Lucie Aldous, Simon H. Hawke, Emma Torzillo, Geoffrey D. Parker, G. Michael Halmagyi PII: DOI: Reference:

S0022-510X(17)34492-1 doi:10.1016/j.jns.2017.12.009 JNS 15697

To appear in:

Journal of the Neurological Sciences

Received date: Revised date: Accepted date:

3 September 2017 7 December 2017 7 December 2017

Please cite this article as: Amy Kunchok, Helen C. Castley, Lucie Aldous, Simon H. Hawke, Emma Torzillo, Geoffrey D. Parker, G. Michael Halmagyi , Fatal reversible cerebral vasoconstriction syndrome. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi:10.1016/ j.jns.2017.12.009

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ACCEPTED MANUSCRIPT Fatal Reversible Cerebral Vasoconstriction Syndrome

Amy Kunchok1,MB BS, Helen C. Castley2, MB BS, FRACP, Lucie Aldous3, MB BS, FRACP, Simon H. Hawke4, MB BS, DPhil (Oxon), FRACP, Emma Torzillo 5, MB BS, Geoffrey D. Parker 6 MB BS, FRANZCR,G. Michael Halmagyi7, MD, FRACP

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Author Affiliations: 1Amy Kunchok, Department of Neurology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. 2Helen C. Castley, Department of Neurology, Royal Hobart Hospital, Hobart, Tasmania, Australia. 3Lucie Aldous, Department of Neurology, Royal Hobart Hospital, Hobart, Tasmania, Australia. 4Simon H. Hawke, Vascular Immunology Unit, Discipline of Pathology, Sydney Medical School and the Brain and Mind Centre, The University of Sydney and Central West Neurology & Neurosurgery and Orange Health Service, Orange, New South Wales, Australia. 5Emma Torzillo, Department of Neurology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia and Orange Health Service, Orange, NSW, Australia. 6Geoffrey D. Parker, Department of Radiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. 7G. Michael Halmagyi, Department of Neurology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

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Key words: reversible cerebral vasoconstriction syndrome; primary angiitis of the central nervous system; vasculitis; thunderclap headache; headache; corticosteroids. Contact details:

Corresponding author: Dr Amy Kunchok1 Neurology Department, Royal Prince Alfred Hospital Camperdown, NSW 2050, Australia [email protected] Phone: +61 409095249

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Present address: Royal Melbourne Hospital, Parkville, VIC, 3050, Australia

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ACCEPTED MANUSCRIPT Helen C. Castley Neurology Department, Royal Hobart Hospital Hobart, 7000, Tasmania, Australia. [email protected]

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Simon Hawke Central West Neurology & Neurosurgery Orange, NSW, 2800, Australia [email protected]

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Lucie Aldous Neurology Department, Royal Hobart Hospital Hobart, 7000, Tasmania, Australia. [email protected]

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Emma Torzillo 2 Neurology department, Royal Prince Alfred Hospital Camperdown, NSW 2050 [email protected]

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Geoffrey D. Parker Radiology Department Royal Prince Alfred Hospital Camperdown, NSW 2050, Australia [email protected]

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G. Michael Halmagyi Neurology Department, Royal Prince Alfred Hospital Camperdown, NSW 2050, Australia University of Sydney [email protected]

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Contributions: AK contributed to conception, design, acquisition of data, drafting the manuscript and revising it critically. HCC collated the data of cases 2 and 3. LA collated the data of cases 2 and 3. SHH contributed to drafting of manuscript and revising the article critically. ET collated the data for case 4. GP revised the article and reviewed the neuroimaging. GMH contributed to conception, drafting of manuscript and revising the article critically. Sources of support/financial or intellectual conflicts of interest: AK, GMH, ET, GDP, SHH LA and HCC – Nil relevant 2

Present address: The Austin Hospital, Heidelberg, VIC, 3084, Australia

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Acknowledgments. We thank Dr Aneesh B. Singhal of the Harvard Medical School for helpful advice and constructive criticism of an earlier version of our article.

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We thank Dr Simon Hammond (Orange Health Service) and Dr Justin Garber (Royal Prince Alfred Hospital and Orange Health Service) for providing clinical information.

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Introduction

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Reversible vasoconstriction syndrome (RCVS) typically presents with a recurrent severe, sudden onset thunderclap headache (TCH) which reaches maximal intensity in under one minute and can be associated with seizures and focal neurological deficits(1). Risk factors include postpartum state and use of vasoconstrictive drugs (triptans, cannabis, SSRIs, amphetamines and nasal decongestants)(2, 3). Neuroimaging typically demonstrates multifocal stenoses particularly of the medium sized cerebral arteries(4), referred to as a “string and beads” or “sausage on a string” appearance(2). RCVS can result in ischemic stroke, convexal subarachnoid haemorrhage, intracerebral or subdural haemorrhage or posterior reversible encephalopathy syndrome(1). Despite its distinct clinical and radiological features, RCVS is still under recognized and mistaken for primary angiitis of the central nervous system (PACNS)(5).

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RCVS is generally benign and reversible. Reports of fatality are rare and the true case fatality rate is unknown. A large retrospective cohort study of 67 RCVS cases did not report any deaths(2), however a two-centre retrospective study of 139 RCVS cases reported 3 deaths(3). Prognostic factors are not well elucidated. Of the few individual reported fatal cases, several were associated with the postpartum state(6-10), marijuana use (11, 12), triptans (12), migraine history (6, 11, 12) and SSRIs (11). Most recently, a single-centre retrospective study of 162 patients has demonstrated an association between corticosteroid treatment and poor angiographic and clinical outcomes(13).

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Case 1

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Patients

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Here we present 4 cases of fulminant, eventually fatal RCVS presenting with TCH not recognized initially and subsequently diagnosed as PACNS and treated with corticosteroids. These cases add to the literature of fatal RCVS cases and emphasize the importance of diagnosing RCVS early, distinguishing it from PACNS and avoiding potentially harmful treatment with corticosteroids.

A 61 year old female developed a sudden severe headache and was found by family curled up on the floor clutching her head in agony. She was taken to the local rural hospital. Nine days previously she had been admitted to the same hospital for three days with a lower respiratory tract infection and treated with oral antibiotics. With simple analgesics the headache resolved within a few hours and she was discharged without further investigation or diagnosis. Her medical history included rheumatoid arthritis treated with gomalimumab, methotrexate and celecoxib, depression treated with escitalopram, hypertension treated with irbesartan and migraine. Two days later she presented, for the 2nd time with ongoing intermittent severe headaches. A non-contrast computed tomography (CT) brain did not

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demonstrate subarachnoid haemorrhage and she was discharged the same day. Three weeks later she presented, for the 3rd time, now with right hemiparesis and aphasia and was transferred to a regional hospital where brain magnetic resonance imaging (MRI) demonstrated watershed infarcts at the junction of the left anterior cerebral artery (ACA) and middle cerebral artery (MCA) territories (Figure 1A). The MR angiogram showed narrowing of the right A1, both proximal A2, left A1 and M1 arterial segments (Figure 1B). Cerebrospinal fluid (CSF) showed 5 white cells, 320 red cells, protein 0.45g/L, normal glucose with negative oligoclonal bands. A diagnosis of PACNS vasculitis was made and the patient was treated with intravenous (IV) methylprednisolone 1gram daily for three days. She continued to have TCHs with blood pressure surges. She became obtunded after the second dose of methylprednisolone and needed to be intubated. CT now showed bilateral loss of grey-white matter difference in a watershed distribution. The patient was then transferred to our tertiary hospital.

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Progress imaging with a CT angiogram showed vasospasm of left proximal MCA and both ACA branches and to a lesser extent in the right proximal MCA branch vessels as well as bilateral widespread watershed infarcts (Figure 1C). Due to arrival timing, she was unable to have a catheter angiogram. RCVS was diagnosed and an intravenous nimodipine infusion was started. She remained obtunded with absent brainstem reflexes, bilateral lower-limb sustained clonus and extensor plantar reflexes and died the next day – 4 weeks after the onset of headache. Autopsy was refused.

Figure 1: Case 1

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Figure 1A – Magnetic resonance imaging axial diffusion weighted image showing typical “string of pearls” appearance in the left cerebral hemisphere involving the deep white matter and cortex consistent with watershed infarction at the interface of the left anterior and middle cerebral arterial supply territories and the left middle and posterior cerebral arterial supply territories. Figure 1B – Magnetic resonance angiography maximum intensity projection image showing marked narrowing of right A1, proximal A2 on both sides, and left A1 and M1 arterial segments consistent with vasospasm (red arrows). Figure 1C – Axial computed tomography scan showing bilateral completed watershed infarction at the interface between the anterior and middle cerebral arteries and anterior and posterior cerebral arteries on both sides. Case 2

A 24 year old male with a history of marijuana use, presented to a tertiary hospital with a history of fluctuating severe headache associated with nausea and vomiting for three days. Non-contrast CT brain and CSF analysis were normal and he was treated with simple analgesia and discharged.

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Nine days later he presented for the 2 nd time, with recurrent TCH, photopsias and vomiting. A diagnosis of migraine was made and again he was treated with simple analgesia and discharged.

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He presented for the 3 rd time, 12 days after the onset of headache, with confusion, slurred speech, ataxia and visual disturbance. MRI/MRA demonstrated multiple areas of infarction - left temporal, right frontal, bilateral occipital and right cerebellar, and markedly attenuated branches of both posterior cerebral arteries (PCAs). CSF was normal. A diagnosis of PACNS was made and IV methylprednisolone 1gram daily and cyclophosphamide 1.5grams were started. A digital subtraction angiogram (DSA) confirmed narrowing of the basilar, PCA and superior cerebellar arteries, A1 and M1 segments of the ACA and MCA bilaterally (Figure 2A). An IV nimodipine infusion was commenced. He deteriorated with expressive aphasia and right upper limb weakness and became agitated and haemodynamically unstable and was intubated. CT now showed widespread infarction with oedema (Figure 2B, 2C, 2D, 2E). Despite decompressive craniotomies (Figure 2F) he died, 18 days from the onset of headache. Post mortem revealed extensive haemorrhagic infarction across multiple territories but no vasculitis and a final diagnosis of RCVS was made.

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Case 3

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Figure 2: Case 2 Figure 2A – Digital subtraction angiogram showing severe vasospasm involving middle and distal portions of the basilar artery (red arrow) and the proximal posterior cerebral arteries and superior cerebellar arteries bilaterally. Figures 2B and 2C – Axial computed tomography showing early acute infarction with hypodensity involving the cortex of the parieto-occipital regions bilaterally. Figures 2D and 2E – After an interval the completed infarction in the PCA territories and in the PCA/MCA watershed territories and in the right ACA territory are more evident. Figure 2F – Bilateral decompressive craniectomies have been performed. There is completed infarction in the occipital and posterior temporal lobes bilaterally.

A 63 year old female presented to a regional hospital with severe headache three days after nasal septoplasty and reported use of nasal decongestants. She was discharged home. She presented for the 2nd time, to a regional hospital six days later, with recurrent throbbing diffuse headache, photophobia, phonophobia, blurred vision and vomiting. Non-contrast CT showed a small haemorrhage in the right parietooccipital lobe. MR angiography and venography was normal apart from the haemorrhage. She was then transferred to a tertiary hospital.

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She continued to have recurrent TCH and developed left sided paraesthesia, weakness and progressive confusion. MRI brain showed the right occipital lobe haemorrhage and progressive bilateral occipital infarctions (Figure 3A). CSF showed 3 white cells, 5 red blood cells and protein 0.16g/L. A diagnosis of PACNS was made and IV methylprednisolone 1gram daily was started. DSA showed bilateral ACA occlusions, multiple bilateral MCA stenoses and a 70% stenosis of the basilar artery (Figure 3B). Cyclophosphamide was added. She became obtunded and CT brain now showed right ACA infarction and extension of the previously identified bilateral occipital infarctions (Figure 3C). A dural biopsy showed no evidence of inflammation and a diagnosis of RCVS was made. The patient died 15 days from the onset of the headache. An autopsy was refused.

Figure 3: Case 3 Figure 3A: Magnetic resonance imaging diffusion weighted image showing right median occipital lobe haemorrhage with surrounding oedema and bilateral occipital infarctions Figure 3B: Digital subtraction angiogram showing diffuse vasospasm of bilateral ACA, MCA and basilar arteries (red arrows). Figure 3C: Computed tomography showing progressive multi-territory cerebral infarction Case 4

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ACCEPTED MANUSCRIPT A 55 year old woman presented to a regional hospital with recurrent TCH, speech disturbance, chest and abdominal pain and paroxysmal hypertension (up to 200/100 mmHg). She had a background of Sjogren’s disease, pulmonary embolism with Factor V Leiden deficiency treated with short term anticoagulants which had ceased, migraine, depression treated with sertraline, and two episodes of Takotsubo cardiomyopathy.

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Between the TCHs she had a normal neurological examination. MRI and CT angiogram were both normal on admission and 10 days later. CSF was also normal apart from positive oligoclonal bands. Vasculitic screen revealed an antinuclear antibody of 1:2560 (previously 1:640), positive Ro and La antibodies and a negative anti-neutrophil cytoplasmic antibody. Inflammatory markers were not raised.

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TCHs persisted during the 4 th week of the admission and electroencephalogram showed continuous theta and delta slowing over both cerebral hemispheres, consistent with encephalopathy . Repeat MRI (her 3rd) showed multiple small acute, infarcts in the left ACA and MCA watershed territory, the corona radiata, and in right parietal-occipital lobe, with haemorrhagic transformation (Figure 4A). CT angiogram now showed widespread focal stenoses of the intracranial arteries, particularly the ACAs and MCAs bilaterally. DSA demonstrated severe multifocal stenoses involving all intracranial arteries. She was treated for presumed PACNS with cyclophosphamide 1gram and a 3 day course of 1gram methylprednisolone followed by an oral taper. One week after the commencement of corticosteroid and cyclophosphamide therapy she deteriorated over 24 hours with progressive aphasia and quadriparesis.

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MRI/MRA (her 4th) now showed extensive hemispheric watershed and cerebellar infarcts with more narrowing of all intracranial blood vessels (Figure 4B and 4C). She needed to be intubated and was treated with two further doses of methylprednisolone 1gram and with one dose of rituximab 1gram. She then developed gross cerebral oedema with tonsillar herniation and died 6 weeks from the first TCH. A retrospective diagnosis of RCVS was made.

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Figure 4: Case 4 Figure 4A – Magnetic resonance imaging diffusion weighted image showing restricted diffusion in the left corona radiata white matter in the location typical for early watershed infarction at the junction between the left ACA and MCA territories. Posteriorly there is restricted diffusion in right parieto-occipital region with low signal intensity on diffusion weighted images due to haemorrhagic infarction. Figure 4B – Magnetic resonance angiography maximum intensity projection showing vessel narrowing involving the M2 segments of both middle cerebral arteries and to a minor extent in the distal right vertebral artery. Figure 4C – Magnetic resonance imaging diffusion weighted image showing very extensive acute infraction with restricted diffusion in the distal branch territories of both middle cerebral arteries. DISCUSSION

While RCVS is rarely fatal, we present 4 fatal RCVS cases that all followed a similar evolution. They all presented to an emergency department 2-3 times over days to weeks with recurrent severe TCH, but none were suspected to have RCVS. After development of neurological deficits, imaging demonstrated multiple acute cerebral infarcts due to multiple stenoses of medium sized arteries. At this point all were diagnosed as PACNS and treated with corticosteroids and 3 with cyclophosphamide as well. A fulminant course followed with widespread cerebral ischemia, infarcts and death. These cases highlight some key issues in the diagnosis and management of RCVS. 10

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Reversible Cerebral Vasoconstriction Syndrome and Thunderclap headache

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Our 4 patients all presented several times with recurrent sudden severe headache reaching maximum intensity in less than 1 minute – i.e. TCH(14). The TCH of RCVS is typically recurrent and triggered by exertion, Valsalva, coughing, sex and emotion. While TCH can be benign, it suggests a neurovascular disorder (15) such as subarachnoid haemorrhage which accounts 11-25% of TCH. Other causes of TCH include cerebral venous sinus thrombosis, cervical artery dissection, acute hypertensive crisis, pituitary apoplexy and colloid cysts of the third ventricle(16). Initial evaluation of TCH should include a non-contrast CT and CSF analysis. In RCVS CT is usually normal, although mild, convexal, nonaneurysmal, subarachnoid haemorrhage can be seen in the sulcal spaces. The CSF is usually normal or near-normal. Reversible Cerebral Vasoconstriction Syndrome versus Primary Angiitis of the CNS

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PACNS is, by definition, confined to the CNS – there is no systemic involvement. The headache in PACNS is insidious, slowly progressive and sometimes associated with encephalopathy and cognitive dysfunction(17). In contrast RCVS triggers severe, recurrent TCH which is often so acute and intense that patients present for emergency medical attention(5). RCVS patients are younger and more often female(18) and it is associated with the postpartum state or exposure to vasoconstrictive drugs such as cocaine, amphetamines, marijuana and serotonergic antidepressants(5). PACNS occurs more often in older males (19) and less often presents with focal neurological deficits(5). Serology and acute phase reactants are normal in PACNS vasculitis (20). CSF in biopsy-proven PACNS can show a lymphocyte predominant pleocytosis, elevated protein and normal glucose (19), however CSF can normal or near-normal in both PACNS and RCVS. Cerebral and meningeal biopsy is the gold standard for diagnosing PACNS, however, the sensitivity is low (~50%)(21).

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A retrospective cohort study of 159 RCVS and 47 PACNS cases found that recurrent or single TCH, with normal imaging, or border-zone infarcts or vasogenic oedema has a 100% positive predictive value for RCVS(5). Neuroimaging with arteriography can aid diagnosis of RCVS: CTA or MRA can be diagnostic but only DSA can demonstrate the exact distribution and severity and provide a route for intra-arterial therapy. The angiographic changes of RCVS are more proximal, severe and symmetrical than in PACNS and importantly, these changes reverse on serial imaging (5, 22). Intra-arterial nimodipine, nicardipine and milrinone have been used to differentiate vasculitis from RCVS(23-25). In PACNS, angiography can show irregular and notched small to medium sized arteries(5). However, angiography has a low specificity (~30%) in PACNS(21) and can be normal in biopsy-proven cases, presumably due to involvement of only small arteries beyond the resolution of angiography(26). High resolution vessel wall MRI may be an additional useful modality to aid in distinguishing RCVS from PACNS (27, 28).

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Reversible Cerebral Vasoconstriction Syndrome Management

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Treatment of RCVS is based on observational studies and is supportive, including the removal of any vasoconstrictive drugs and avoiding known triggers. Triptans should not be used for headache, as they have been associated with RCVS(29). Intravenous and oral nimodipine has been reported to improve vasoconstriction(30). Case studies of intra-arterial vasodilator therapy have shown potential benefit from using nimodipine, milirinone and verapamil (3136). A retrospective cohort study showed that corticosteroids are associated with clinical and angiographic worsening of RCVS (13) and should be avoided in the management of RCVS. Conclusion

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In summary, in a patient presenting with TCH, it is important to consider RCVS, which although is usually benign, can be fatal. These 4 cases highlight key issues in diagnosis and management including distinction from PACNS and the potentially detrimental role of corticosteroids.

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RCVS is not necessarily benign. Although vasoconstriction may be reversible it might also result in fatal ischaemia. RCVS should be considered in any patient presenting with severe, acute onset, recurrent headaches RCVS must be distinguished from primary CNS vasculitis RCVS should be managed without using corticosteroids

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