Drug-resistant epilepsy, early-onset hypertension and white
matter lesions: a hidden paraganglioma
Journal: BMJ Case Reports
Manuscript ID bcr-2018-228348.R1
Manuscript Type: Reminder of important clinical lesson
Date Submitted by the
25-Apr-2019
Author:
Complete List of Authors: Silvennoinen, Katri; UCL Queen Square Institute of Neurology,
Department of Clinical and Experimental Epilepsy; The Chalfont Centre
for Epilepsy,
Waghorn, Alison; Royal Liverpool University Hospital
Balestrini, Simona; UCL Queen Square Institute of Neurology,
Department of Clinical and Experimental Epilepsy; The Chalfont Centre
for Epilepsy,
Sisodiya, Sanjay; UCL Queen Square Institute of Neurology, Department
of Clinical and Experimental Epilepsy; The Chalfont Centre for Epilepsy,
Keywords:

Epilepsy and seizures < Neurology, Hypertension < Cardiovascular
medicine

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Full clinical cases submission template
TITLE OF CASE Do not include “a case report”

Drug-resistant epilepsy, early-onset hypertension and white matter lesions: a hidden
paraganglioma
SUMMARY Up to 150 words summarising the case presentation and outcome (this
will be freely available online)

We describe the case of a 35-year-old man with focal epilepsy since age 16. Due to a refractory
course, several treatments were tried over the years, including insertion of a deep brain stimulator
(DBS). At the time of his first assessment at our unit, he had recently been diagnosed with
hypertension. An MR scan of brain revealed multiple T2 hyperintense white matter lesions, and
evidence of previous haemorrhage in the left basal ganglia and pons. On follow-up imaging, the
changes were considered to be in keeping with hypertensive arteriopathy. He was referred for
further assessment of his hypertension and was found to have a para-aortic paraganglioma. This
was excised 16 months after his initial presentation to us. The surgery was associated with an
improvement in his seizure control. This case serves as a reminder of the need to be vigilant about
the possibility of coexisting conditions in people with epilepsy.
BACKGROUND Why you think this case is important – why did you write it up?

Epilepsy is a common neurological disorder, with a worldwide lifetime prevalence of 7.6 per
1000.[1] In a quarter of people newly diagnosed with epilepsy, seizures persist despite
appropriate medical treatment.[2] Among other factors, certain comorbidities are known to
influence epilepsy prognosis,[3] and indeed comorbid conditions in epilepsy are common, with a
cumulative prevalence of up to 50%.[3] This case illustrates the need to remain vigilant to the
possibility of diverse other conditions in people with epilepsy, even in specialist settings and with
established epilepsy diagnoses.
CASE PRESENTATION Presenting features, medical/social/family history

A 35-year-old right-handed man was referred to a tertiary epilepsy centre for re-assessment of his
refractory epilepsy. There was no family history of note. His antecedent history was
unremarkable apart from two self-terminating febrile seizures before the age of 1 year. At age 16,
he presented with two unprovoked generalised tonic–clonic seizures occurring within 24 hours.
He started antiepileptic drug treatment, and subsequently his seizures have predominantly been
focal cognitive seizures with impaired awareness. The latter have proved refractory to treatment,
whilst his generalised tonic–clonic seizures have occurred only sporadically since the initiation of
antiepileptic drugs.
An MR scan of brain and EEG, aged 20, were reported as normal. Scalp videotelemetry aged 22
failed to localise seizure onset. He underwent intracranial EEG recording on two occasions; first
with bilateral temporal depth electrodes and later also with bilateral frontal and subfrontal strips.
The final results suggested bilateral onset and he was not considered to be a candidate for
resective surgery. A vagal nerve stimulator (VNS) was inserted aged 29. This proved ineffective
and was subsequently switched off. Four years later, he underwent insertion of deep brain
stimulator (DBS) electrodes to bilateral ventral anterior thalamic nuclei. Following DBS
insertion, there was a change in his seizure semiology, with new types of brief episodes, ‘drop
attacks’, during which he became vacant, his head deviated to the right and he would collapse.
DBS also proved ineffective and was removed 3 years later.
On presentation at our centre, aged 35, his antiepileptic treatment was phenytoin, sodium

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valproate, clobazam, levetiracetam and carbamazepine. He had previously also tried at least
lacosamide, lamotrigine, topiramate, perampanel, and retigabine. However, he continued to
experience daily drop attacks resulting in injuries. He carried an existing diagnosis of
hypertension, for which he took perindropril. According to GP records, ‘essential hypertension’
was formally diagnosed 3 months before his presentation to us. His family recalled that at the
time of DBS insertion 3 years before, his blood pressure was elevated, and attributed to ‘white
coat syndrome’.
INVESTIGATIONS If relevant

He was admitted to our unit for investigations. Ambulatory EEG showed a slow background and
interictal sharp activity with varying side emphasis. Several habitual seizures were captured, with
EEG correlate of generalised spike wave discharge followed by a run of fast activity. Tachycardia
was not reported in association with EEG changes or seizures. An MR scan of brain showed
previous haemorrhage in the left basal ganglia and central pons, multiple T2-hyperintense lesions
in the white matter of both hemispheres with a periventricular and peripheral distribution, and
changes consistent with previous insertion and removal of DBS. His previous MR scans, the last
preceding DBS insertion by 7 months, were reported as normal.
CSF examination showed only mildly elevated protein of 0.46 g/L (reference range 0.13-0.4) and
a slightly increased CSF/serum albumin ratio of 7.33 (reference range <7.2). Screening for serum
autoantibodies and antineuronal antibodies was negative. A repeat MR scan of brain 4 months
after his admission showed new areas of T2 hyperintensity in the right basal ganglia, and two
microhaemorrhages in the left thalamus and temporal lobe (Figure 1). He was reviewed by the
neurovascular team: hypertensive arteriopathy was diagnosed, and treatment for hypertension was
escalated with amlodipine.
Further multispecialty assessment revealed, 1 year after his admission, persistently elevated
concentrations of fractionated normetadrenalines, with plasma normetadrenaline at 5880.1
pmol/L (reference range <1180.0). Plasma metadrenaline and 3-methoxytyramine concentrations
were normal. Subsequent imaging, including abdominal SPECT/CT, demonstrated a partly
calcified mass, anterior to the aorta and medial to the inferior vena cava, at the level of the L1/2
intervertebral disc. Metaiodobenzylguanidine (123I-MIGB) scintigraphy was in keeping with a
diagnosis of a paraganglioma.
DIFFERENTIAL DIAGNOSIS If relevant

Differential diagnoses of DBS-related white matter change and of an inflammatory CNS disease
were considered, but the absence of evidence in support of the latter, and the absence of reports of
such MRI changes in association with DBS made further search for the cause of his MRI
abnormalities necessary.
TREATMENT If relevant

The patient underwent open surgery for the tumour 16 months after his initial presentation at our
centre. The tumour measured 50x37x32 mm and was completely excised. Immunocytochemistry
was positive for CD56 and chromogranin, confirming the diagnosis of paraganglioma. The Ki67
index was 10%. Apart from several foci of vascular invasion, there were no adverse histological
features.
OUTCOME AND FOLLOW-UP

Following surgery, his metadrenaline concentrations returned to normal. In the ensuing 6 months,
his blood pressure also normalised and antihypertensive treatment was stopped. The surgery was
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associated with significant improvement in his seizure frequency: at last follow-up, 8 months
after surgery, he was experiencing seizures on 1–2 days per month in contrast to several times per
week prior to surgery.
DISCUSSION Include a very brief review of similar published cases

Paragangliomas are neuroendocrine tumours arising within the sympathetic or parasympathetic
paraganglia. Sympathetic paragangliomas are derived from chromaffin cells and secrete
catecholamines; histologically and functionally similar tumours arising from the adrenal medulla
are historically known as phaeochromocytomas.[4,5] There is a significant genetic component,
with an estimated 40% of tumours associated with germline mutations in one of several
susceptibility genes, including NF1, RET, VHL, and the SDHx group of genes, which encode the
subunits of succinate dehydrogenase.[4] Among the remaining sporadic cases, somatic mutations
are recognised in a proportion of patients.[4] The prevalence of sympathetic
paragangliomas/phaeochromocytomas among adults with hypertension is 0.2–0.6%.[6] In
addition to episodic or sustained hypertension, patients may present with episodes of headache,
sweating and palpitations.[5] Measurement of plasma free metanephrines or urinary fractionated
metanephrines is a sensitive screening test, with positive results warranting imaging follow-up.[6]
Although metastases are possible, especially in the context of mutations in SDHB, the majority of
tumours are benign.[5] Surgical treatment, with appropriate preoperative medical management, is
the mainstay of treatment.[6]
In keeping with the final diagnosis, our patient had hypertension and repeatedly elevated
metadrenalines. In contrast, there was no history of episodic symptoms attributable to excess
sympathetic activity; his habitual episodes were clinically and electrographically consistent with a
diagnosis of epilepsy.
There are several accounts of seizures in the context of acute crises of
phaeochromocytomas/paragangliomas.[7-9] In contrast, more prolonged disease courses appear
less frequent. One group reported the case of an 8-year-old girl who presented with epilepsy and a
right-sided cervical mass due to a carotid body tumour.[10] Excision of the tumour was
performed 16 months after initial presentation, with complete remission of seizures. In this case,
there was no evidence of excess of catecholamines, and although the authors postulated that
intraoperative manipulation of the vagal nerve contributed to seizure remission, the origin of
epilepsy remains unclear. In another case, a 7-year-old child was commenced on antiepileptic
drugs following an acute presentation with headache, anxiety, palpitations, and unilateral tonicclonic seizures; 2 years later, she was found to have an adrenal ganglioneuroma, with
intraoperative crisis suggestive of catecholamine excess.[11] It is unclear what the course of the
seizure disorder was prior to and following surgery.
Stress is associated with activation of the sympathetic adrenergic pathway of the autonomic
nervous system and the hypothalamic-pituitary-adrenal axis and is a commonly reported seizure
trigger in people with epilepsy [12]. The relationship between catecholamines and seizures
remains incompletely understood. Endogenous noradrenaline release from the locus coeruleus, as
well as pharmacological agents leading to elevated extracellular concentrations of noradrenaline
in the CNS, have been demonstrated to have anticonvulsant effects.[13] Among the adrenergic
receptors, alpha receptors have higher affinity for noradrenaline. The most prevalent receptor
type, α1A, has been consistently shown to exert anticonvulsant effects, attributed to enhancement
of gamma-aminobutyric acid (GABA)-mediated neurotransmission.[13] In contrast, for several
other adrenergic receptors, evidence for effects of activation on seizure activity is less established,
with evidence for pro-convulsant effects for some subtypes.[13] In the context of systemic excess
of noradrenaline, consideration of the possible effects on seizure activity is further complicated
by the fact that brain entry is prevented at the blood-brain barrier (BBB).[13] NoradrenalineRevised September 2014

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induced hypertension may, however, promote entry by means of induced BBB dysfunction.[13]
In addition to other pro-convulsant effects associated with BBB dysfunction, it has been proposed
that this could promote seizure activity by means of inhibition of endogenous noradrenaline
release.[13]
Cerebral small vessel disease (SVD) is emerging as a risk factor for late-onset epilepsy,[14] and
appears to be also associated with delayed seizures following symptomatic intracerebral
haemorrhage.[15] In our patient, there was clear imaging evidence of vasculopathy and
microhaemorrhages. While these appear to have developed much later than the onset of seizures,
it is possible that these secondary effects of hypertension may have contributed to his epilepsy.
Of the genetic causes of paragangliomas, neurofibromatosis 1, caused by mutations in the NF1
gene, is associated with seizures.[16] Our patient’s phenotype was not in keeping with this
syndrome. However, with the rapid increase in the knowledge of genetics of epilepsy,[17] it is
possible that novel associations with other genetic conditions will be uncovered. From this
perspective, the SDHx group of genes are especially interesting, given the links between succinate
and GABA metabolism [18].
This patient with refractory epilepsy and a complex treatment history, including DBS, was found
during the course of his evaluation to have new neuroimaging changes of unknown cause.
Multispecialty assessments led to the diagnosis of hypertensive arteriopathy secondary to a
sympathetic paraganglioma. Establishing the correct diagnosis was key to management, and led
to improvement in seizure control.
LEARNING POINTS/TAKE HOME MESSAGES 3 to 5 bullet points – this is a required
field

1. A paraganglioma is a possible cause of secondary hypertension in adults. Elevated
concentrations of metadrenalines are a clue to diagnosis.
2. People with epilepsy frequently have other medical conditions, which may need evaluation in
their own right.
3. Physicians looking after people with epilepsy have a critical role in identifying these conditions
and ensuring appropriate investigations are arranged.
4. Management of comorbid conditions may lead to improvement in seizure control.

REFERENCES Vancouver style (Was the patient involved in a clinical trial? Please
reference related articles)

1. Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: A systematic
review and meta-analysis of international studies. Neurology 2017;88:296-303.
2. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in
newly diagnosed epilepsy. Neurology 2012;78:1548-54.
3. Keezer MR, Sisodiya SM, Sander JW. Comorbidities of epilepsy: current concepts and future
perspectives. Lancet Neurol 2016;15:106–15.
4. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from
genetics to personalized medicine. Nat Rev Endocrinol 2015;11:101–11.

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5. Welander J, Söderkvist P, Gimm O. Genetics and clinical characteristics of hereditary
pheochromocytomas and paragangliomas. Endocr Relat Cancer 2011;18:R253–76.
6. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014;99:1915–42.
7. Anderson NE, Chung K, Willoughby E, Croxson MS. Neurological manifestations of
phaeochromocytomas and secretory paragangliomas: a reappraisal. J Neurol Neurosurg
Psychiatry 2013;84:452–7.
8. Leiba A, Bar-Dayan Y, Leker RR, Apter S, Grossman E. Seizures as a presenting symptom of
phaeochromocytoma in a young soldier. J Hum Hypertens 2003;17:73–5.
9. Petrie J, Lockie C, Paolineli A, et al. Undiagnosed phaeochromocytoma masquerading as
eclampsia. BMJ Case Reports 2012;2012:bcr1020114922.
10. Wall ML, Davies RS, Warfield AT, Simms MH. Cessation of epilepsy in an 8-year-old girl
following removal of carotid body paraganglioma. Vasc Endovascular Surg 2009;43:103–6.
11. Batra YK, Rajeev S, Rao KL. Anesthesia management of a ganglioneuroma with seizures
presenting as pheochromocytoma. Paediatr Anaesth 2007;17(5):479–83.
12. Galtrey CM, Mula M, Cock HR. Stress and epilepsy: fact or fiction, and what can we do
about it? Pract Neurol 2016;16:270–278.
13. Ghasemi M, Mehranfard N. Mechanisms underlying anticonvulsant and proconvulsant actions
of norepinephrine. Neuropharmacology 2018;137:297–308.
14. Ferlazzo E, Gasparini S, Beghi E, et al. Epilepsy in cerebrovascular diseases: Review of
experimental and clinical data with meta-analysis of risk factors. Epilepsia 2016;57:1205–14.
15. Biffi A, Rattani A, Anderson CD, et al. Delayed seizures after intracerebral haemorrhage.
Brain 2016;139:2694–2705.
16. Pecoraro A, Arehart E, Gallentine W, et al. Epilepsy in neurofibromatosis type 1. Epilepsy
Behav 2017;73:137-141.
17. Myers KA, Johnstone DL, Dyment DA. Epilepsy genetics: Current knowledge, applications,
and future directions. Clin Genet 2019;95:95-111
18. Tretter L, Patocs A, Chinopoulos C. Succinate, an intermediate in metabolism, signal
transduction, ROS, hypoxia, and tumorigenesis. Biochim Biophys Acta 2016;1857:1086-1101.
FIGURE/VIDEO CAPTIONS figures should NOT be embedded in this document

Figure 1. Left: T2-weighted MRI brain image from first admission at our unit, showing multiple
white matter hyperintensities with a peripheral and periventricular distribution (blue arrows).
Middle: on repeat imaging 4 months later, there is a new area of T2 hyperintensity in the head of
the right caudate nucleus and in the anterior putamen (red arrow). Right: susceptibility weighted
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image performed on repeat MRI clearly demonstrates previous left basal ganglia haemorrhages
(white arrow).
PATIENT’S PERSPECTIVE Optional but strongly encouraged – this has to be written
by the patient or next of kin

Copyright Statement
I, Sanjay Sisodiya, The Corresponding Author, has the right to assign on behalf of all authors and does
assign on behalf of all authors, a full assignment of all intellectual property rights for all content within
the submitted case report (other than as agreed with the BMJ Publishing Group Ltd) (“BMJ”)) in any
media known now or created in the future, and permits this case report (if accepted) to be published
on BMJ Case Reports and to be fully exploited within the remit of the assignment as set out in the
assignment which has been read. http://casereports.bmj.com/site/misc/copyright.pdf.

Date: 25/04/2019

PLEASE SAVE YOUR TEMPLATE WITH THE FOLLOWING FORMAT:
Corresponding author’s last name and date of submission, eg,
Smith_September_2017.doc

Revised September 2014

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99x41mm (600 x 600 DPI)