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\begin{document}

\title{Diffuse large B cell lymphoma presenting with hypersomnia}



\author[1]{Swasthi S Kumar}%
\author[1]{Praveen Kumar}%
\author[1]{Sanjay  Sriram}%
\author[1]{Upendra Baitha}%
\affil[1]{All India Institute of Medical Sciences}%


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  \date{May 28, 2024}


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\emph{Diffuse large B cell lymphoma presenting with hypersomnia}

\textbf{Short title: DLBCL presenting with hypersomnia}

\textbf{Swasthi S Kumar\textsuperscript{1} MD, Praveen
Kumar\textsuperscript{2}DM, Sanjay Sriram\textsuperscript{3}MD, Upendra
Baitha\textsuperscript{4} MD}

\emph{\textsuperscript{1}Junior resident, Department of General
Medicine, All India Institute of Medical Sciences, New Delhi, India --
110029, swasthiskumar@gmail.com}

\emph{\textsuperscript{2} Senior resident, Department of General
Medicine, All India Institute of Medical Sciences, New Delhi, India --
110029, praveenkuma.124@gmail.com}

\emph{\textsuperscript{3} Senior resident, Department of Pathology, All
India Institute of Medical Sciences, New Delhi, India -- 110029,
sanjay10.cena@gmail.com}

\emph{\textsuperscript{4} Additional professor, Department of General
Medicine, All India Institute of Medical Sciences, New Delhi, India --
110029, drupendraraj14@gmail.com}

\textbf{Correspondence to} : \emph{Dr Upendra Baitha, Additional
Professor, Department of General Medicine, All India Institute of
Medical Sciences, New Delhi, India - 110029}

\emph{E-mail: drupendraraj14@gmail.com}

\textbf{Funding} : \emph{None}

\textbf{Data availability statement:} Data is available from the
corresponding author on reasonable request

\textbf{Consent:} Consent has been taken from the patient to publish
case details and images.

\textbf{Conflict of interest:} The authors declare no conflict of
interest.

\textbf{Author contributions:} SSK, PK and UB were directly involved in
the patient's care. SSK and PK wrote up the manuscript under the
guidance of UB. SS performed the histopathological examination of lymph
nodes, provided the relevant images, and helped prepare the manuscript.
All authors have read and approved the final manuscript.

\textbf{Key words:} \emph{``Hypersomnia''; ``narcolepsy''; ``Diffuse
large B cell lymphoma''; ``lymphoma''; ``chemotherapy''}

KEY CLINICAL MESSAGE:

Hypersomnia is an atypical presentation of CNS lymphoma. Involvement of
the hypothalamus causing reduced orexin secretion could be the likely
cause. Our case demonstrates that in patients presenting with
hypersomnia, after ruling out common causes, it is essential to look for
CNS malignancies before labelling it as primary narcolepsy.

INTRODUCTION:

Excessive daytime sleepiness (EDS), alternatively known as hypersomnia
or hypersomnolence, is defined as the inability to maintain wakefulness
and alertness during the significant waking hours of the day for at
least three months (ICSD-3 definition). EDS is reported by 10-25\% of
the population, with equal prevalence in males and females{[}1{]}. The
most common cause of EDS is insufficient sleep at night due to shift
work or a medical illness like heart failure causing orthopnea. Other
causes for hypersomnia are sleep disorders like obstructive sleep apnea
(OSA), central disorders of hypersomnolence like narcolepsy or Kleine
Levin syndrome, psychiatric conditions like depression or anxiety,
medical disorders like Parkinson's disease, multiple sclerosis,
hypothyroidism or intake of drugs like benzodiazepines. We present an
interesting case of a middle-aged lady with no prior comorbidities who
presented to us with hypersomnia but did not appear to have any symptoms
or signs suggestive of the common causes of hypersomnia, and a
preliminary workup for the same turned out to be negative.

CASE REPORT:

A middle-aged lady, who was a homemaker without comorbidities, presented
with complaints of hypersomnia for the last three months. Her husband
initially noticed that she had excessive daytime sleepiness and would
fall asleep while watching television, reading newspapers, and was
taking prolonged afternoon naps. Gradually, it worsened such that she
would not even get up from bed in the morning and would not eat meals or
communicate with family members. She did not give any history of
insufficient sleep during night-time. There was no history of sleep
paralysis, cataplexy, hallucinations, excessive snoring, cessation of
breaths, involuntary leg movements or enactment of dreams during sleep.
She did not give any history of unintentional weight gain, constipation
or menorrhagia. No history of jaundice, abdominal distension or
hematemesis. No history of memory loss, cognitive deficits, focal
neurological deficits, hyperphagia, hypersexuality, depression, mania,
trauma or any drug intake before the onset of symptoms. She was not an
alcoholic or smoker and did not give any history of substance abuse.

On examination, her pulse rate was 82 beats/min, and her blood pressure
and respiratory parameters were within normal limits. She was stuporous
and would only open her eyes and respond to questions on giving a
prolonged stimulus in the form of pain. The head-to-toe examination was
within normal limits and showed no pallor, icterus, clubbing, oedema or
generalised lymphadenopathy. A detailed neurological examination
couldn't be done owing to her stuporous state, but her pupils were
bilaterally reactive, reflexes preserved, and plantar reflexes were
down-going bilaterally. Assessment of other systems was within normal
limits and did not reveal hepatosplenomegaly.

Routine investigations showed normal haemoglobin (13.6g/dL), leukocyte
count of 8330 cells/uL and platelet count of 1,80,000 cells/uL. Her
renal function tests were normal, but liver function tests showed
transaminitis (SGOT- 180U/L, SGPT- 212U/L) with normal bilirubin
(1.2mg/dL). Thyroid profile, serum cortisol and ammonia levels were
normal. The urine toxicology screen did not show the presence of any
commonly used drugs like opioids. As the history was not suggestive of
sleep-related breathing disorder or central disorder of hypersomnolence,
tests like polysomnography or multiple sleep latency tests were not
done. As a preliminary workup did not yield a cause for the hypersomnia,
CEMRI was done. It showed an ill-defined T2/FLAIR hyper-intensity
involving bilateral basifrontal white matter, anterior part of the
corpus callosum, bilateral globus pallidi and hypothalami showing
homogenous contrast enhancement and mild diffusion restriction with
associated ventriculitis (figure 1) and the possible differentials were
malignancy (?CNS lymphoma), infection like tuberculosis, or a
demyelinating lesion like multiple sclerosis. CSF evaluation showed no
cells, protein -- 68mg/dL, and sugar 80mg /dL. CSF acid fast bacilli
(AFB), geneXpert, gram stain, bacterial culture, bacterial DNA PCR, and
KOH stain were negative.

Malignant cytology of the CSF was negative when repeated on three
separate occasions. CECT chest and abdomen done for evaluation of other
sites of involvement showed abdominal and retroperitoneal
lymphadenopathy and lytic sclerotic lesions in the left femoral head,
right iliac blade and L3 vertebra. Biopsy from the internal iliac lymph
node suggested diffuse large b cell lymphoma(DLBCL), germinal centre
type, with high ki67. Immunohistochemistry showed myc+ (figure 2). Thus,
a Lugano stage IV DLBCL diagnosis was made, and the patient was
transferred under the care of the medical oncology department.

She was started on triple intrathecal therapy with cytarabine 100mg,
methotrexate 12mg, steroids (hydrocortisone 15mg), and systemic
chemotherapy -- R-HCVAD/MA regimen (Rituximab
375mg/m\textsuperscript{2}, Hyper-fractionated Cyclophosphamide
300mg/m\textsuperscript{2}, Vincristine 1.4mg/m\textsuperscript{2},
Doxorubicin 50mg/m\textsuperscript{2}, Dexamethasone 40mg, alternating
with Methotrexate 1g/m\textsuperscript{2}, Cytarabine
3g/m\textsuperscript{2}). There was a mild improvement in her stuporous
state after the first cycle of chemotherapy. Spontaneous eye opening was
present, and there was an improvement in following motor commands. The
patient was discharged after the first cycle. At her last follow-up
visit, after three cycles of chemotherapy, the patient has much
symptomatic improvement. She has no complaints of hypersomnia at present
and is in the process of returning to her regular daily routine.

DISCUSSION:

DLBCL is the most common type of non-Hodgkin's lymphoma (NHL). It is
more common among males; the median age at presentation is over 60.
DLBCL arises from mature B cells and can arise de novo or as a
transformation of other low-grade lymphomas. It usually presents as
rapidly enlarging lymphadenopathy in the neck, abdomen or mediastinum. B
symptoms like fever, weight loss and night sweats are seen in 30\%, and
60\% of the patients have advanced disease at presentation. DLBCL
invading the CNS can involve the brain, leptomeninges, eyes or spinal
cord. The common presenting symptoms are focal neurological deficits,
neuropsychiatric symptoms, headache, seizures, altered behaviour and
ocular symptoms. Hypersomnia is an atypical and rare presentation of
DLBCL.

Orexin A and B (hypocretin 1 and 2) are excitatory neurotransmitters in
the lateral hypothalamus. They are secreted in the awake state and help
maintain a wakefulness state. They also increase the activity of locus
coeruleus, raphe nucleus and tuberomammillary nucleus, which also
promote a state of wakefulness. A deficiency of orexin-secreting neurons
resulting in reduced orexin levels is the proposed aetiology for
narcolepsy type 1. Cerebrovascular accidents, tumours, vascular
malformations, infections or inflammatory diseases affecting the
posterior hypothalamus can damage the orexin-secreting neurons leading
to narcolepsy, called secondary narcolepsy. Our patient did not fit the
diagnostic criteria for narcolepsy as she did not have features like
cataplexy, and a multiple sleep latency test couldn't be done owing to
the stuporous state of the patient at presentation. The periventricular
lesion encroaching upon the hypothalamus, causing reduced orexin
secretion, could be the likely cause of hypersomnia in our patient.

There are some rare reports of CNS lymphomas involving the hypothalamus
presenting with hypersomnia or narcolepsy{[}2,3{]}. Onofrj et al.
reported the first case of a 30-year-old male who presented with
narcolepsy, which was diagnosed as secondary to a temporal lobe lymphoma
one year later{[}4{]}. This case was similar to ours, where narcolepsy
was the only presenting complaint of the patient; however, early brain
imaging helped in a prompt diagnosis and initiation of treatment of CNS
lymphoma. Hamada et al. reported a case of relapsed primary intraocular
lymphoma with hypersomnolence. Still, the patient also had other
neurological findings, like the rigidity of lower limbs, hyperreflexia
and positive Babinski sign.

Interestingly, MRI or FDG-PET scan identified no hypothalamic lesion in
this patient. However, the CSF orexin levels were low and returned to
normal following chemotherapy{[}5{]}. In most cases, the symptoms of
hypersomnia and narcolepsy are resolved with chemotherapy directed
against the primary malignancy. Our case highlights the importance of
ruling out secondary causes, especially CNS malignancies, even in
patients presenting with only hypersomnia and no other neurological
signs or symptoms before labelling them as primary narcolepsy or
hypersomnia.

REFERENCES:

\begin{enumerate}
\tightlist
\item
  Young TB. Epidemiology of daytime sleepiness: definitions,
  symptomatology, and prevalence. J Clin Psychiatry. 2004;65 Suppl
  16:12-6. PMID: 15575799.
\item
  Dauvilliers Y, Abril B, Charif M et al. Reversal of symptomatic
  tumoral narcolepsy, with normalization of CSF hypocretin level.
  Neurology. 2007 Sep 18;69(12):1300-1. doi:
  10.1212/01.wnl.0000276948.46213.64. PMID: 17875919.
\item
  Ospina-Garc\selectlanguage{ngerman}ía N, Román GC, Pascual B et al. Hypothalamic relapse of a
  cardiac large B-cell lymphoma presenting with memory loss,
  confabulation, alexia-agraphia, apathy, hypersomnia, appetite
  disturbances and diabetes insipidus. BMJ Case Rep. 2018 Aug
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\item
  Onofrj M, Curatola L, Ferracci F et al. Narcolepsy associated with
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\item
  Hamada Y, Takata T, Kawakita R et al. Orexin secretion abnormality
  involved in excessive somnolence in CNS lymphoma without hypothalamic
  lesions. J Clin Neurosci. 2019 Jun;64:6-7. doi:
  10.1016/j.jocn.2019.03.066. Epub 2019 Apr 5. PMID: 30962060.
\end{enumerate}

LEGENDS:

Figure 1: Axial CEMRI images show enhancement of the ependymal lining
(arrow), and deep grey matter areas, including the lentiform nuclei and
left caudate head (arrowheads). MR spectroscopy reveals an elevated
choline peak (white arrow).

CECT abdomen reveals multiple non-necrotic mildly enhancing
intraperitoneal, bilateral common iliac and left external iliac nodes
(*).

Figure 2: Microphotographs showing (A) Diffuse large B-cell lymphoma
(x40) and its corresponding immunohistochemistry profiles (x20), (B)
CD20, (C) CD3, (D) CD10, (E) CD Bcl-6, (F) C-MYC, (G) MUM-1, (H) Ki67
proliferative index (approximately 90-95\%)

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