Central Nervous System Involvement of Multiple Myeloma Presenting as Short-lasting Unilateral Neuralgiform Headache with Conjunctival Injection and Tearing: A Case Report

Abstract

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are part of the trigeminal autonomic cephalalgia (TAC) group of headache disorders. Attacks present with repeated, severe, sharp, stabbing, or throbbing pain. Patients may experience a single attack, recurrent attacks with pain-free interictal periods, or a sawtooth pattern background pain with superimposed stabs.^1,2

Although SUNCT typically presents as a primary headache disorder, it may be secondary to an underlying pathology, such as pituitary tumors or posterior fossa lesions, both intra and extra-axial (vascular lesion, tumor, or bony abnormalities). Multiple Myeloma (MM) with central nervous system involvement (CNS MM) most commonly presents with visual changes (36%), radiculopathy (27%), headache (25%), confusion (21%), dizziness (7%) and seizures (6%).^3,4 Secondary SUNCT cases have been sparsely described (less than 60), and CNS MM presenting as SUNCT has not been previously described in the literature.^2,5

Our case describes a previously unreported clinical presentation of CNS MM. The report highlights the need for a timely and thorough diagnostic work-up of headache in patients with risk factors for a secondary etiology, which in this case included new-onset, autonomic features, older age, and history of malignancy. A misdiagnosis will preclude a potentially life-extending or saving targeted therapy for the underlying illness. We also aim to remind practitioners of the variability in the clinical symptoms of SUNCT, which are known to occur in a significant number of cases, including migrainous features and dull interictal pain.

Introduction

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are part of the trigeminal autonomic cephalalgia (TAC) group of headache disorders (Reviewed in Table 1). They are relatively uncommon, have slight male predominance, with onset between 40 and 70 years and a prevalence of 0.05 to 1 in 1000. Attacks present with repeated, severe, sharp, stabbing, or throbbing pain. Patients may experience a single attack, recurrent attacks with pain-free interictal periods, or a sawtooth pattern background pain with superimposed stabs.^1,2

Table 1.

Trigeminal Autonomic Cephalalgia (TAC) Characteristics

Trigeminal autonomic cephalalgias (TAC)	Pain Location	Attack Duration	# attacks fulfilling criteria	Description	Autonomic Features	Frequency	Migrainous Features	Exacerbants	Other features	Sex ratio (F:M)
Short-lasting unilateral neuralgiform headache attack syndromes (SUNHA)	Unilateral, V1	1-600 seconds	At least 20	Single stabs, series of stabs or in a sawtooth pattern	At least 1, ipsilateral to the pain: 1, 2, 3, 4, 5, 6, 7	At least once a day (Typical Dozens to hundreds per day)	Rarely	Cutaneous, thermal, mechanical		1 to 1.5
Cluster	Unilateral, frontal / temporal / periorbital	Minutes to hours	At least 5	15-180 minutes (when untreated)	A sense of restlessness / agitation OR at least 1, ipsilateral to the pain: 1, 2, 3, 4, 5, 6, 7	1 every other day up to 8 per day	Sometimes	Alcohol, sleep		1:2 to 1:7
Hemicrania continua	Unilateral	Minutes to days	>3 months	Continuous pain with superimposed attacks	At least 1, ipsilateral to the pain: 1, 2, 3, 4, 7	Up to dozens per day	Often	Variable	Prevented absolutely by therapeutic doses of indomethacin	2 to 1
Paroxysmal hemicrania	Unilateral, frontal / temporal / periorbital	2-30 min	At least 20	Continuous pain with superimposed attacks	At least 1, ipsilateral to the pain: 1, 2, 3, 4, 7	>5 per day (Typical 1-40 per day)	Sometimes	Neck turning	Prevented absolutely by therapeutic doses of indomethacin	1 to 1.5

Adapted from ¹³

(1) Conjunctival injection and/or lacrimation, (2) Nasal congestion and/or rhinorrhea, (3) Eyelid edema, (4) Forehead and facial sweating, (5) Forehead and facial flushing, (6) Sensation of fullness in the ear, (7) Miosis and/or ptosis

Although SUNCT typically presents as a primary headache disorder, it may be secondary to an underlying pathology, such as pituitary tumors or posterior fossa lesions, both intra and extra-axial (vascular lesion, tumor, or bony abnormalities). Multiple Myeloma (MM) with central nervous system involvement (CNS MM) most commonly presents with visual changes (36%), radiculopathy (27%), headache (25%), confusion (21%), dizziness (7%), and seizures (6%).^3,4 Secondary SUNCT cases have been sparsely described (less than 60), and CNS MM presenting as SUNCT has not been previously described in the literature.^2,5

Our case describes a previously unreported clinical presentation of CNS MM. The report highlights the need for a timely and thorough diagnostic work-up of headache in patients with risk factors for a secondary etiology, which in this case included new-onset, cranial autonomic features, older age, and history of malignancy. A misdiagnosis will preclude a potentially life-extending or saving targeted therapy for the underlying illness. We also aim to remind practitioners of the variability in the clinical symptoms of SUNCT, which are known to occur in a significant number of cases, including migrainous features and dull interictal pain.

Case

A 56-year-old man with no prior history of headache and recent diagnosis of multiple myeloma on cyclophosphamide, bortezomib, and dexamethasone (CyBorD) therapy, complicated by progressive chronic kidney disease (CKD), anemia, lytic osseous lesions of sternum, and pleural plasmacytomas bilaterally, presented with new onset severe headache.

The patient reported 10 out of 10 pain to the left orbit characterized by 50–100 severe, short stabbing attacks each lasting seconds to 1 minute with a dull, left frontal, interictal background pain of moderate intensity. The patient reported unilateral tearing, conjunctival injection (eye redness), ptosis, and rhinorrhea, occurring at least 10 times daily in association with some of the attacks. Worsening at night, the pain would often awaken him from sleep. He also had intermittent migrainous symptoms including photophobia, phonophobia, and nausea. Occasionally during or before attacks, he experienced impaired concentration, vertigo, or a visual aura of flashing lights. His pain was exacerbated by lying down and improved by a dark quiet environment.

Prior to headache presentation, the MM was thought to be clinically responsive to chemotherapy and the oncologist was planning for a stem cell transplant. Shortly after the initial onset of headache, the patient underwent magnetic resonance imaging (MRI) of the brain (without gadolinium given CKD), which was unremarkable.

Over several months following the onset of headache, preventive therapies trialed included topiramate, verapamil, lamotrigine, and one dose of galcanezumab 240 mg, all without significant benefit. Abortive therapies trialed included sumatriptan, frovatriptan, caffeine/acetaminophen/aspirin, and medical marijuana. The patient was eventually referred to the Jefferson Headache Center for inpatient headache management.

Upon admission, due to concern for secondary headache, he underwent further diagnostic workup, including repeat imaging and lumbar puncture. Computed tomography of the head (CTH) non-contrast revealed lytic bony lesions, most prominently in the clivus (Figure 1A, B). The lumbar puncture revealed an opening pressure of 30 cm H20, a pleocytosis with 148 WBC (lymphocytic), protein of 181, glucose of 43. Cytology and flow cytometry resulted with 68% abnormal plasma cells. The day following the LP, his interictal pain decreased from a 6 to a 3.

Figure 1.

CT without contrast of the head Sagittal SCOUT (A) and Axial (B) at the time of diagnosis of CNS MM with lytic lesions, most prominently in the clivus (arrow); MRI brain with and without gadolinium contrast axial images (B) T2 FLAIR, (C) T1 Post-contrast, 2 months after diagnosis of CNS MM, depicting small 4 mm enhancing lesion in the L middle cerebral peduncle.

He was medically treated with multiple infusions including, continuous lidocaine, repetitive-dose dihydroergotamine (DHE) and haloperidol with improvement of his interictal headache from 6/10 pain on admission to 0/10 by the completion of the 5-day hospitalization with complete resolution of severe SUNCT attacks for 24 hours prior to discharge. He was prescribed oral mexiletine as a new daily preventive however, his pain resurfaced back up to 6/10 within 12 hours of discharge.

The week following discharge, his oncologist initiated treatment with intrathecal methotrexate. The patient reported rapid headache relief following the first dose treatment and by his second session, he achieved total resolution of headache attacks and pain over the following several weeks. Approximately 2 months after his hospitalization, he had an MRI brain with and without gadolinium contrast, which revealed a new 4 mm lesion in the left middle cerebellar peduncle with central enhancement (Figure 1B/C).

At the time of writing this report, (5 months following the CNS MM diagnosis, and 11 months following the onset of headache) our patient continues to receive intrathecal and systemic chemotherapeutic agents and has remained headache free.

Discussion

The incidence of secondary headache disorders in patients older than 50 has not been specifically described, however, one retrospective review of 1898 patient cases of ages over 65 from a single tertiary headache center classified 58 patients (16%) with a secondary headache classification. ⁶

Our case serves as a reminder for clinicians to consider secondary headache causes for patients with new-onset headache disorders, utilizing screening tools for red-flag symptoms (Table 2). Our patient had concerning historical factors such as: older age without personal headache history, sudden/new/severe onset, comorbid malignancy, treatment-refractory, cranial autonomic features, and worsening at night and with lying down. We would encourage work-up in patients with red flag symptoms or clinical characteristics concerning for possible secondary causes to include (if clinically appropriate): contrast-enhanced brain imaging with MRI (and CT if there is concern for bony lesions), dedicated vessel imaging (in certain circumstances), and/or lumbar puncture (with opening pressure assessment, +/- cytological analysis) prior to diagnosing a primary headache syndrome.

Table 2.

Headache “Red Flags” for secondary causes: 2 SNOOP 4 RED FLAGS

	Sign or Symptom	Related Secondary Headaches (Most Relevant ICHD-3b categories)
1	Systemic symptoms including fever	Headache attributed to infection or non-vascular intracranial disorders, carcinoid or pheochromocytoma
2	Neoplasm in history	Neoplasms of the brain; metastasis
3	Neurologic deficit or dysfunction (including decreased consciousness)	Headaches attributed to vascular, non-vascular intracranial disorders; brain abscess and other infections
4	Onset of headache is sudden or abrupt	Subarachnoid hemorrhage and other headaches attributed to cranial or cervical vascular disorders
5	Older age (after 50 years)	Giant cell arteritis and other headache attributed to cranial or cervical vascular disorders; neoplasms and other non-vascular intracranial disorders
6	Pattern change or recent onset of headache	Neoplasms, headaches attributed to vascular, non-vascular intracranial disorders
7	Positional headache	Intracranial hypertension or hypotension
8	Precipitated by sneezing, coughing, or exercise	Posterior fossa malformations, Chiari malformation
9	Papilledema	Neoplasms and other non-vascular intracranial disorders; intracranial hypertension
10	Progressive headache and atypical presentations	Neoplasms and other non-vascular intracranial disorders
11	Pregnancy or peuperium	Headaches attributed to cranial or cervical vascular disorders; post-dural puncture headache; hypertension-related disorders (eg. Preeclampsia); cerebral sinus thrombosis; hypothyroidism; anemia; diabetes
12	Painful eye with autonomic features	Pathology in posterior fossa, pituitary region, or cavernous sinus; Tolosa-Hunt syndrome; ophthalmic causes
13	Post-traumatic onset of headache	Acute and chronic post-traumatic headache; subdural hematoma and other headache attributed to vascular disorders
14	Pathology of the immune system such as HIV	Opportunistic infections
15	Painkiller overuse or new drug at onset of headache	Medication overuse headache; drug incompatibility

Abbreviation: ICHD3-3b = International Classification of Headache Disorders 3b

From ¹⁴

In CNS MM, reported clinical presentations have varied. Published case series have described vision changes, radiculopathies, headaches, confusion, altered consciousness, cranial nerve palsies, gait disorders, weakness, vertigo, seizures.^3,4 The median age of CNS MM diagnosis is around 53 years, although the average age of MM onset is 65-70 years, with median diagnosis between initial MM and CNS involvement about 2 years. Approximately 20% of patients have CNS involvement at the time of MM diagnosis in a retrospective multi-institutional study of 172 patients. ³ A different study found 0.7% of 4060 patients at a tertiary center had identifiable CNS involvement of MM, with plasma cells in the CSF detected in 87% of cases and MRI findings with CNS involvement noted in 82% of the patients. ⁷ Most commonly, CNS MM on CT and MRI manifests with pachymeningeal and leptomeningeal enhancing deposits followed by intraparenchymal brain lesions and direct extra-axial extension of disease from the adjacent bony calvarium.^7-9 Unfortunately, CNS MM often portends a poor median survival, as low as 1 to 5 months, ¹⁰ with treatments including intrathecal methotrexate. ¹¹

We hypothesize that the pathophysiology explaining our patient’s symptoms are more likely related to either his left cerebral peduncle lesion or his leptomeningeal involvement of disease, as evidenced by elevated CSF opening pressure (Figure 1B, C). In prior reports of secondary SUNCT/SUNA, cases have mostly been reported in pituitary and posterior fossa lesions. It has been postulated that SUNCT syndromes involve the hypothalamus, trigeminovascular system, carrying pseudo-unipolar trigeminal primary afferents from the trigeminocervical complex (TCC), and cranial autonomic system, involving connections of the TCC with the superior salivary nucleus and sphenopalatine ganglion. Activation of the hypothalamus can activate the TCC and stimulate the trigeminal autonomic reflex, resulting in ipsilateral pain and cranial autonomic symptoms. ² Potentially, the brainstem lesion could involve the TCC, triggering this secondary pain syndrome. Another alternative would be that the patient’s leptomeningeal involvement triggered a secondary headache disorder explaining the patient’s background pain and associated feature of worsening when lying down, but the subsequent high CSF pressure exacerbated a primary SUNCT syndrome. Given that the patient’s symptoms resolved with intrathecal treatment of his malignancy, it is favored the patient had a secondary headache directly related to his CNS MM, rather than a primary headache disorder.

Cases of SUNCT/SUNA have demonstrated exquisite response to IV lidocaine therapy (with efficacy in up to 90% of patients). ¹² Our patient tolerated both IV lidocaine and IV DHE and experienced transient resolution of headache which rapidly recurred following cessation of the infusions. Ultimately, treatment with intrathecal chemotherapy resulted in sustained pain relief.

In summary, our case represents an atypical presentation of CNS MM and a previously unreported etiology of SUNCT/SUNA headache. This serves as a reminder to practitioners to perform an exhaustive diagnostic work-up of headaches with red-flag features before diagnosing a primary headache syndrome. This applies even when the specific secondary cause of concern is rare, as is the case with CNS MM.

ORCID iD

Victor S. Wang https://orcid.org/0000-0002-1823-8557