Neurogenic orthostatic hypotension as a rare presentation of Waldenström macroglobulinemia associated with light-chain amyloidosis: A diagnostic challenge

INTRODUCTION

The most common subtype of lymphoplasmacytic lymphoma is Waldenström macroglobulinemia (WM), which involves immunoglobulin M (IgM) monoclonal gammopathy. Waldenström macroglobulinemia with associated AL amyloidosis (WM-AL) is distinct from the typical AL amyloidosis because it is underlying a lymphoplasmacytic neoplastic clone and shows higher rates of soft tissue, lymph node, lung, and peripheral nerve involvement.^[1] The autonomic nervous system can be affected due to small fiber nerve involvement related to WM-AL, similarly to a pure autonomic failure (PAF), another very rare condition, for which it is estimated that fewer than 10,000 people have this diagnosis in the United States.^[2,3]

CASE REPORT

A 70-year-old Caucasian man with a history of hypertension for the past 10 years and peripheral arterial disease diagnosed 5 years ago, as well as dyslipidemia and back pain. He presented for his first autonomic evaluation in our clinic. His family history was unremarkable. He had smoked one pack of cigarettes daily for 50 years and consumed two units of alcohol daily for the past 30 years. He reported a progressive decline in his sense of smell over the previous 30 years, occasional acting-out dreams, and constipation for the past 5 years.

His primary complaint was orthostatic intolerance, described as “a wave of weakness overcoming me.” He started having dizziness, lightheadedness, weakness, and fatigue after standing up or walking for prolonged periods in the past 9 years. Those symptoms worsened in the summer and improved with drinking water, sitting, or lying down. Over the past year, he has experienced frequent fainting episodes. His primary cardiologist conducted an extensive evaluation to rule out structural heart, carotid, and coronary causes, which yielded inconclusive results.

Physical and neurological examinations were unremarkable. A magnetic resonance imaging brain scan was normal. Sitting, blood pressure (BP) was 164/84 mmHg, with a heart rate (HR) of 84 bpm. Supine BP average was 157/85 mmHg, with an HR of 64 bpm. HR variability during deep paced breathing was normal for his age, indicating preserved parasympathetic innervation of the heart. BP overshoot after Valsalva maneuver (VM) strain release was absent, suggesting impaired baroreflex-mediated sympathetic activation. Tilted, BP at 3 minutes was 95/58 mmHg with an HR of 73 bpm. After 10 minutes, BP was 111/59 mmHg with an HR of 71 bpm. He reported lightheadedness, pain at the top of his neck, and weakness in his legs, which resolved on returning to the supine position. There was a 51 mmHg drop in systolic BP (SBP) and a 25 mmHg drop in diastolic BP, with a HR increase of 2 bpm (ΔHR/ΔSBP ratio = 0.09). Sudoscan and quantitative sensory testing (QST) revealed severe foot denervation.

Laboratory tests identified mild normochromic normocytic anemia and high levels of IgM. Furthermore, serum electrophoresis showed an M component and elevated free kappa light chains [Table 1]. Bone marrow flow cytometry revealed 23% of lymphoplasmacytic cells with kappa light chain restriction and a positive mutation for MYD88. An 18F-Flourodeoxiglucose Positron Emission Tomography Scan (18-FDG PET) scan showed radiotracer uptake in the spleen, portocaval, and periportal lymph nodes. After ruling out wild-type amyloidosis, monoclonal gammopathy of unknown significance, and multiple myeloma paraproteinemic neuropathy, a WM-AL diagnosis was made. The patient began treatment with zanubrutinib 80 mg daily and midodrine 5 mg 3 times daily as well as non-pharmacologic measures, that is, liberalized water intake, added dietary salt, and use of leg compression stockings. The antihypertensive medication was adjusted to improve supine hypertension. He gradually improved over the following months, with no further syncope episodes and remission of the WM-AL.

Table 1: Assessments.

DISCUSSION

PAF is a neurodegenerative disease due to abnormal alpha-synuclein protein deposition in sympathetic and parasympathetic nerves, leading to neurogenic orthostatic hypotension (nOH). As PAF progresses, systemic involvement affects the gastrointestinal, genitourinary, sudomotor, secretomotor, and vasomotor systems. Hematological involvement results in normocytic normochromic anemia according to Biaggioni et al.^[4] Animal models explained the role of the sympathetic system in erythropoiesis; sympathetic beta-adrenergic receptor agonism in the renal juxtaglomerular cells; thus, PAF patients often exhibit a blunted erythropoietin response.

Our patient presented symptoms of synucleinopathies and impaired cardiovascular sympathetic reflexes, leading to a diagnosis of nOH with severe supine hypertension. VM showed absent late phase II and phase IV overshoot, suggesting severe denervation; however, these findings could not differentiate between afferent or efferent baroreflex failure, nor between central or peripheral neuronal damage from a primary neurodegenerative disease versus a systemic condition [Figure 1]. PAF exhibits reduced or absent sweating, like autonomic peripheral neuropathies.^[4] Sudoscan indicated postganglionic damage, and the QST evaluation suggested a non-length-dependent sensitive neuropathy; both clues required excluding alternative differential diagnoses, that is, hematological disorders, autonomic autoimmune ganglionopathy, and paraneoplastic syndromes.^[5]

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Figure 1:

VM patterns across conditions (created with BioRender.com). (a) Healthy subjects: Preserved late phase II indicates a normal sympathetic response. (b) Pure autonomic failure (PAF). (c) Lewy body dementia (LBD). (d) Our patient has AL amyloidosis associated with waldenström macroglobulinemia (AL-WM). (e) Afferent baroreflex failure (ABF) post-treatment for tonsillar carcinoma. All patients had absent late phase II and IV overshoot, suggesting severe sympathetic cardiovascular response. VM: Valsalva maneuver.

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WM is associated with monoclonal immunoglobulin M (IgM) protein. In addition, fatigue due to normocytic anemia is the most common symptom;^[6] other manifestations include hepatomegaly (20%), splenomegaly (15%), and lymphadenopathy (15%). Only 3% of cases present with pure neurogenic involvement, as seen in our patient.^[6] Bone marrow and lymph nodes show pleomorphic B-lineage cells expressing B-cell markers (CD19+, CD20+, CD3−, and CD104−). In addition, the MYD88 mutation is detectable in 93% of patients. WM treatment depends on clinical symptoms. While smoldering WM requires surveillance, an IgM-related paraproteinemia causing neuropathy or anemia may warrant rituximab monotherapy. Further, a bulky disease or hyperviscosity-related WM involves a combination of bendamustine and rituximab, or a second line with zanubrutinib may be appropriate.^[7,8] Our case is very similar to a case reported by Jacob et al.^[9] They reported a 72-year-old male with autonomic neuropathy related to AL amyloidosis-related Waldenström macroglobulinemia diagnosed 20 years before. He has had frequent syncope episodes due to nOH and skin accumulation of AL amyloid; the autonomic assessment showed a clear autonomic sympathetic dysfunction, like our case. That supported evidence that this presentation would be missed as not present a systemic involvement, as in our case.

CONCLUSION

nOH is commonly the hallmark of autonomic failure and synucleinopathies. However, our patient with AL-WM had a postganglionic denervation, a sensitive neuropathy, and mild anemia as soft findings, which requires careful interpretation before concluding a PAF diagnosis. Therefore, a detailed hematological and imaging workup emphasizes keeping another differential diagnosis in mind. This case is a reminder of the complexity of autonomic dysfunction and the importance of maintaining an open diagnostic mindset to uncover treatable causes.