pii: jc-17- 00489http://dx.doi.org/10.5664/jcsm.7006

CAS E R EPOR T S

A Case of Narcolepsy Type 2 and Postural Tachycardia Syndrome Secondary
to Lesions of the Thalamus and Amygdala
Paul Kim, MD1; Emmanuel During, MD1,2; Mitchell Miglis, MD1,2

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1
Department of Neurology & Neurological Sciences, Stanford University Medical Center, Palo Alto, California; 2Stanford Center for Sleep Sciences and Medicine, Department of
Psychiatry and Behavioral Sciences, Stanford University Medical Center, Palo Alto, California

Although there are reports of narcolepsy type 1 caused by lesions of the central nervous system, there are far fewer reports of narcolepsy type 2 (NT2)
caused by discrete brain lesions. We report a case of a patient in whom NT2 was diagnosed after a viral illness, and inflammatory lesions in the right
thalamus and amygdala were found. In addition, symptoms of autonomic impairment developed and postural tachycardia syndrome was subsequently
diagnosed in this patient. To our knowledge this is the first reported case of NT2 resulting from central nervous system lesions in these discrete locations, as
well as the first reported case of postural tachycardia syndrome associated with narcolepsy.
Keywords: autonomic, immune-mediated, inflammatory, narcolepsy, postural tachycardia syndrome
Citation: Kim P, During E, Miglis M. A case of narcolepsy type 2 and postural tachycardia syndrome secondary to lesions of the thalamus and amygdala.
J Clin Sleep Med. 2018;14(3):479–481.

score was 18. Oral examination revealed Mallampati class 4.
Neurological examination was notable for hypoesthesia along
the left hemiface and hemibody.
Brain magnetic resonance imaging with contrast, performed
4 months after symptom onset, demonstrated an 8 × 6 mm hyperintense lesion in the right thalamus and a 4 × 4 mm hyperintense lesion in the right amygdala (Figure 1). Neither of these
lesions enhanced with contrast. No lesions were visualized in
the hypothalamus. Overnight polysomnogram performed at
this time, after discontinuing all medications for 1 week, demonstrated a total sleep time of 8.8 hours, sleep onset latency of
10 minutes, sleep efficiency of 98%, and REM sleep latency
of 278 minutes. There was no sleep-disordered breathing or
periodic limb movements. A Multiple Sleep Latency Test
(MSLT) performed the following day demonstrated a mean
sleep latency of 4.6 minutes and 4 out of 4 sleep onset rapid eye
movement periods. Her serum HLA-DQB1*06:02 was negative. Lumbar puncture performed 1 month later was normal,
with no oligoclonal bands. Cerebrospinal fluid hypocretin was
measured at this time and was also normal (335 pg/mL).
Autonomic testing demonstrated an exaggerated postural
tachycardia on 70-degree head-up tilt. The maximum recorded
heart rate was 128 bpm, from a baseline of 72 bpm (56 beat increase), with a normal blood pressure response, consistent with
POTS. Valsalva maneuver demonstrated an exaggerated blood
pressure decrement in phase II. Heart rate variability with deep
breathing and measures of sweat function with quantitative sudomotor axon reflex testing were both normal.
Prior to our evaluation she was treated with a 4-week course
of prednisone, which had no effect on her symptoms. She
was continued on her usual dose of amphetamine-dextroamphetamine; higher doses resulted in paradoxical sleepiness.

I N T RO D U C T I O N
Narcolepsy type 1 (NT1) is caused by selective loss of hypocretin-producing neurons in the lateral hypothalamus.1 The
anatomy and pathophysiology of narcolepsy type 2 (NT2) is
less understood, with heterogeneous clinical phenotypes. The
available literature on NT2 caused by other neurological conditions, otherwise known as symptomatic or secondary narcolepsy, is limited, and there are no reports to our knowledge of
postural tachycardia syndrome (POTS) associated with NT2.
We present an illustrative case of discrete central nervous system lesions leading to secondary NT2 and POTS.
R E P O R T O F CAS E
An 18-year-old woman with a prior diagnosis of attention-deficit hyperactivity disorder and anxiety was referred to the sleep
clinic for evaluation of excessive daytime sleepiness that began approximately 5 days after an upper respiratory infection
(URI). Her sleepiness progressed over several weeks to the
point that she reported sleep attacks in both passive and active
situations, despite sleeping up to 18 hours a day. She experienced vivid dreams and sleep paralysis, but denied hypnic hallucinations or cataplexy. Several weeks later she experienced
daily headaches, difficulty concentrating, night sweats, palpitations, and orthostatic lightheadedness. Her prior medications
included 20 mg of sustained-release amphetamine-dextroamphetamine, 50 mg of sertraline, and an oral contraceptive,
which she continued during her illness and without dose adjustment. Physical examination demonstrated a thin woman with
a body mass index of 19 kg/m2. Her Epworth Sleepiness Scale
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P Kim, E During and M Miglis

Case Report

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Figure 1—Brain magnetic resonance images.

Axial T2-weighted brain magnetic resonance images showing an 8 × 6 mm ovoid lesion in the right posterior superior thalamus (left image), and a 4 × 4 mm
lesion in the right amygdala (right image). Lesions indicated by arrows.

Modafinil was added but later discontinued due to lack of efficacy. After 9 months of symptoms, sodium oxybate was added
and titrated to 3 g twice nightly, resulting in significant improvement in her daytime sleepiness and sleep fragmentation.
Propranolol was prescribed for her postural tachycardia, leading to improvement in her orthostatic symptoms.

Guilleminault and colleagues have reported on the “pseudohypersomnia” of patients with bilateral paramedian thalamic
lesions,4 in which patients demonstrated reduced sleep onset
latency during MSLT, but did not develop REM intrusion or
sleep onset rapid eye movement periods, as our patient did.
Bassetti and colleagues similarly described a series of patients
with paramedian thalamic strokes and hypersomnia; however,
those patients with unilateral lesions had mild hypersomnia
that resolved by 8 months.5 There are no reports of unilateral
thalamic lesions associated with secondary narcolepsy that we
are aware of. Our patient’s lesion was located in the lateral and
posterior-dorsal thalamus, an area that contains the intralaminar nucleus, which projects to arousal centers including the reticular activating system, hypothalamus, and basal forebrain.6
Our patient’s other lesion was located in the amygdala, an
area that is particularly dense in hypocretin fibers and receptors. There are reciprocal connections between the amygdala
and brainstem areas involved in the regulation of REM sleep,
such as the pedunculopontine tegmentum and laterodorsal tegmental nuclei; lesions in this region have been noted to impair
arousal.7 Bilateral amygdala lesions in primates result in more
consolidated sleep, greater sleep efficiency, increased total
sleep, and increased REM density.8 In addition, and of particular interest in our case, the amygdala contains nuclei that project to autonomic centers in the hypothalamus and brainstem

D I SCUS S I O N
We present the case of a patient in whom NT2 and POTS developed after a viral illness, likely because of immune-mediated lesions in the thalamus and amygdala. Although there are
several reports of NT1 secondary to discrete central nervous
system lesions, to our knowledge this represents one of few
reported cases of NT2 due to this etiology. Most reports of
secondary NT1 and excessive daytime sleepiness involve lesions in the hypothalamus, although bilateral thalamic lesions
have also been described. Scammel and colleagues published
the case of a patient in whom NT1 developed after a large
postoperative stroke that involved the bilateral thalamus and
amygdala; however, the hypothalamus and areas of the basal
forebrain and rostral midbrain were also involved.2 Watson
and colleagues described a case of a neurocysticercosis leading to NT2, but this lesion was located in the hypothalamus.3
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P Kim, E During and M Miglis

Case Report

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Copyright 2024 American Academy of Sleep Medicine. All rights reserved.

that regulate physiological responses to fear, stress, and emotion. Autonomic impairment has been described in narcolepsy,
and hypocretin pathways project to areas in the brainstem and
spinal cord that regulate sympathetic tone, including the rostral medulla, solitary nucleus, and sympathetic preganglionic
neurons.9 Researchers have demonstrated that microinjection
of hypocretin into these areas in mice can depolarize some of
these synapses and result in tachycardia or hypertension.10
The pathogenesis of narcolepsy in our patient did not involve measurable hypocretin deficiency. In addition, although
the imaging studies may lack sensitivity, no hypothalamic lesions were found. Although it is a possibility that the patient’s
MSLT findings were due to a rebound effect after discontinuing her stimulant and antidepressant medications, we think this
is less likely given the fact that these medications were stopped
1 week prior to testing. In addition, the doses of these medications remained stable before and after her URI symptoms,
whereas her hypersomnia began distinctly 5 days after URI
symptoms and persisted without improvement. Given prior
publications supporting the role of the amygdala and thalamus
in the regulation of sleep and autonomic tone, we propose that
our patient’s lesions resulted in her unique presentation of hypersomnia and autonomic impairment.

3. Watson NF, Doherty MJ, Zunt JR. Secondary narcolepsy following
neurocysticercosis infection. J Clin Sleep Med. 2005;(1)1:41–42.
4. Guilleminault C, Quera-Salva MA, Goldberg MP. Pseudo-hypersomnia
and pre-sleep behaviour with bilateral paramedian thalamic lesions. Brain.
1993;116(Pt 6):1549–1563.
5. Bassetti C, Mathis J, Gugger M, Lovblad KO, Hess CW. Hypersomnia
following paramedian thalamic stroke: a report of 12 patients. Ann Neuro.
1996;39(4):471–480.
6. Jang SH, Lim H W, Yeo SS. The neural connectivity of the intralaminar
thalamic nuclei in the human brain: a diffusion tensor tractography study.
Neurosci Lett. 2014;579:140–144.
7. Bisetti A, Cvetkovic V, Serafin M, et al. Excitatory action of hypocretin/
orexin on neurons of the central medial amygdala. Neuroscience.
2006;142(4):999–1004.
8. Benca RM, Obermeyer WH, Shelton SE, Droster J, Kalin NH. Effects of
amygdala lesions on sleep in rhesus monkeys. Brain Res. 2000;879(1–
2):130–138.
9. Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE. Amygdala
lesions reduce cataplexy in orexin knock-out mice. J Neurosci.
2013;33(23):9734–9742.
10. Carrive P. Orexin, orexin receptor antagonists and central cardiovascular
control. Front Neurosci. 2013;7:257.

SUBMISSION & CORRESPONDENCE INFORMATION
Submitted for publication September 14, 2017
Submitted in final revised form November 10, 2017
Accepted for publication November 15, 2017
Address correspondence to: Mitchell Miglis, 213 Quarry Road, Palo Alto, CA 94304;
Email: mmiglis@stanford.edu

R E FE R E N CES
1. Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and
hypersomnia, and their implications in the hypothalamic hypocretin/orexin
system. Sleep Med Rev. 2005;9(4):269–310.
2. Scammell TE, Nishino S, Mignot E, Saper CB. Narcolepsy and low CSF
orexin (hypocretin) concentration after a diencephalic stroke. Neurology.
2001;56(12):1751–1753.

Journal of Clinical Sleep Medicine, Vol. 14, No. 3

D I SCLO S U R E S TAT E M E N T
All authors have seen and approved this manuscript. The authors report no conflicts
of interest.

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