From perimenopause to neuroinflammation: Rethinking a case of late‐onset mania

Abstract

Background

This case report explores the evolution of diagnoses in a 46‐year‐old female whose perimenopausal symptoms and psychiatric history shaped the diagnostic interpretation, delaying recognition of her underlying neurologic condition.

Case Presentation

This patient, who had been stable for over a decade on a serotonin reuptake inhibitor (SSRI), first experienced mania that warranted hospitalization at age 46. She appeared to have late‐onset mania, as perimenopausal symptoms preceded the episode. When she developed painless weakness in her legs and became wheelchair bound, the lumbar spine magnetic resonance imaging (MRI) findings were normal, leading to a suspicion of conversion disorder. A later MRI of the brain and neurologic workup ultimately revealed primary progressive multiple sclerosis as the cause of both her psychiatric and physical symptoms.

Conclusion

While there is growing evidence of first‐time perimenopausal onset of mania, it is hard to estimate how many of these cases are attributable to autoimmune illnesses with perimenopausal onset. This case outlines the importance of including a brain MRI and autoimmune serum panel in the workup for women presenting with new‐onset mania in their perimenopausal years.

INTRODUCTION

A late‐onset manic episode after years of psychiatric stability should prompt clinicians to consider a secondary cause rather than primary bipolar disorder. The age‐of‐onset distribution for first‐time mania shows two peaks in incidence: one in young adulthood and another in mid‐ to late life. ¹ The second peak includes a substantial proportion of cases that are not primary bipolar disorder but secondary mania resulting from inflammation, neurological injury, vascular insult, or autoimmune processes. ² The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) advises that late‐onset manic symptoms in late midlife should prompt consideration of other medical conditions. ³ In a review of case reports of late‐onset mania, 82% of cases were suspected to have an underlying organic cause. ⁴

This evaluation is complicated in midlife women, in whom mood symptoms may be attributed to perimenopause and in whom autoimmune diseases, including multiple sclerosis (MS), demonstrate altered presentation around the menopausal transition. We describe a case in which a first manic episode in a woman in her mid‐40s was initially attributed to late‐onset bipolar disorder before the underlying diagnosis of primary progressive multiple sclerosis (PPMS) was established.

CASE PRESENTATION

Ms. S is a 46‐year‐old Caucasian female with a long‐standing history of generalized anxiety disorder who became manic over a 2‐week period, threatened to harm her family, and required emergent detention in a retail store by police for florid delusions and verbal aggression. She had been stable on fluoxetine 40 mg for 12 years prior to this event for generalized anxiety disorder. She had never experienced trauma, past psychiatric hospitalizations, suicide attempts, or manic episodes, and had a negative family history for bipolar disorder. Her manic symptoms included grandiose erotomanic delusions, flight of ideas, sleeping less than 2 h per night, distractibility to the point she could no longer complete activities of daily living, and pressured speech.

She was treated in an inpatient psychiatric facility for over a week with the primary diagnosis of bipolar disorder, most recent episode manic, despite her psychiatric history lacking clear evidence of a depressive episode. Fluoxetine was discontinued, and she stabilized on olanzapine 20 mg. The inpatient team obtained a history of perimenopausal symptoms for the last 3 years, including hot flashes, irritability, and fatigue. Her development of mania was attributed to studies reflecting a bimodal distribution of bipolar disorder, especially in perimenopausal women.

A month before her psychiatric admission, the patient was a passenger in a minor motor vehicle accident. Though she did not sustain physical injury, she had increased anxiety from the accident and frustration over the destruction of her vehicle. No nightmares or flashbacks were noted. Medical workup was negative, and the radiologic report of brain magnetic resonance imaging (MRI) without contrast was negative for acute findings and positive for T2 lesions that “most likely represent small vessel disease in a patient of this given age.” Of note, the patient was not a smoker nor did she have microvascular risk factors such as diabetes or hypertension. While the radiologic interpretation did not indicate a cause for further workup, review of the images (Figure 1) could have led to an earlier, accurate diagnosis.

Figure 1.

Axial FLAIR brain magnetic resonance imaging (MRI) obtained without contrast. Four sequential slices through the cerebral hemispheres demonstrate bilateral periventricular white matter hyperintensities, most prominent as a discrete focus in the right posterior periventricular region, with additional subcortical involvement at the more superior levels.

Over the next few months, the patient experienced painless, progressive weakness in her legs to the point where she required a wheelchair to keep from falling. X‐rays, physical examination, and an MRI of her lumbar spine revealed no injuries or explanation for her inability to walk. The negative medical workup and mental health history led to the diagnosis of a conversion disorder.

For 2 years, the patient's mania remained stable on olanzapine; however, she continued to suffer from delusions of reference and erotomanic delusions. Her speech became dysarthric, and she made no progress in regaining the ability to walk. She continued to carry the diagnosis of bipolar disorder and conversion disorder in the electronic medical record at varied outpatient psychiatric locations.

The patient had not been treated by the author for 6 years prior to her accident. Frustrated with her lack of progress, the patient's family brought her back to the author's clinic seeking a second opinion. Suspecting intracranial pathology, an MRI without contrast of the brain with the indication to “rule out MS vs. malignancy” and a neurology consult including were ordered (Table 1). The hyperintense T2 lesions included “a differential of microvascular ischemic disease or Multiple Sclerosis.” The original lesions 2 years prior can still be visualized in Figure 2 with expansion and atrophy.

Table 1.

Cerebrospinal fluid and serum inflammatory markers obtained during diagnostic workup.

Test	Patient value	Reference range
Oligoclonal bands number, CSF	8 (high)	0–1
CNS IgG synthesis rate	52.6 (high)	<8.0 mg/day
IgG total CSF	13.8 (high)	0.0–6.0 mg/dL
IgG index	2.46 (high)	0.28–0.66
CSF IgG/albumin ratio	0.66 (high)	0.09–0.25
Erythrocyte sedimentation ratea	48 (high)	1.0–20.0
C‐reactive proteina	14.50 (high)	<0.30

Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; IgG, immunoglobulin G.

^a Erythrocyte sedimentation rate and C‐reactive protein was drawn 5 months after diagnosis. At the time, the patient had a urinary tract infection and sacral ulcer.

Figure 2.

Axial FLAIR brain magnetic resonance imaging (MRI) obtained without contrast approximately 2 years after Figure 1. Interval progression is demonstrated by increased confluency and extent of bilateral periventricular white matter hyperintensities compared with Figure 1, with expanded subcortical signal abnormality at the more superior levels and mild ventricular enlargement consistent with cerebral atrophy. The autoimmune and neurology workups, including a lumbar puncture, were consistent with multiple sclerosis.

The late onset, cognitive decline, and muscle weakness were consistent with PPMS. Upon establishment of the PPMS diagnosis, her presentation was retrospectively reclassified as a Manic Episode Due to Another Medical Condition per DSM‐5 criteria, rather than primary bipolar disorder, her decline was refractory to treatment. Within 2 years of diagnosis, the patient passed away.

DISCUSSION

Multiple factors may have contributed to this patient's diagnosis being missed at presentation. In a study examining physician disparities in symptom interpretation, physicians attributed physical symptoms of cardiac disease to a mental health condition in 31.3% of middle‐aged females as opposed to 15.6% of their male counterparts. ⁵ As providers, we must be aware of gender‐based stereotypes and their effect on differential diagnosis. A prospective review of mental health conditions over the menopause transition outlines how important life stressors, health conditions, and role transitions coincide with the timing of menopause. ⁶ , ⁷ In addition to mood symptoms, irritability associated with elevated follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) levels is a hallmark symptom. ⁸ These observations have shaped both provider and patient expectations regarding menopause, contributing to potential anchoring bias. ⁷

While perimenopause is more robustly associated with depressive recurrence than with new‐onset mania in the existing literature, ⁶ , ⁷ when mania does emerge during this transition, organic etiologies warrant consideration before attributing the presentation to primary bipolar disorder.

Adding to the confounding factors of treating women in perimenopause are the transition states of autoimmune diseases. While lupus flares decrease after menopause, the damage they cause increases. Early onset of menopause is significantly associated with rheumatoid arthritis, with more joint destruction occurring in postmenopausal women. Lastly, psoriasis is associated with a postmenopausal exacerbation in incidence. ⁹

The relationship between MS and menopause is particularly relevant to our patient. A British population‐based study reported peak incidence of MS in women between 40 and 55. ⁹ Postmenopausal women with MS have higher severity of symptoms even when adjusting for disease duration, and the disease at onset is more frequently primary progressive rather than relapsing‐remitting. ⁹ Diagnostic confusion is compounded by the overlap between menopausal and MS symptoms of fatigue, affective changes, cognitive difficulties, and vasomotor symptoms. ⁹

Ms. S's long‐term stability on fluoxetine, lack of family history of bipolar disorder, and neurologic symptoms indicated an organic cause to her manic symptoms. Her progression from mania to profound weakness to finally the diagnosis of MS highlights the need for a possible standardized medical workup and close examination of neuroimaging in the setting of new‐onset mania in midlife.

A published case report of MS‐induced mania in a 47‐year‐old woman with pre‐existing MS, whose presentation of paranoia, irritability, and decreased need for sleep was similar to our patient's, further supports this clinical pattern. ¹⁰ To our knowledge, no prior published case reports have specifically documented the intersection of MS‐induced mania during the perimenopausal transition.

MECHANISTIC IMPLICATIONS

There is growing research on the common biological pathways shared by mood disorders and neuroinflammatory disease. Immune‐activated cytokine release disrupts neurotransmission between the limbic and prefrontal circuits that regulate emotion. ¹¹ , ¹² In MS, demyelination in these regions results in symptoms such as impulsivity, grandiosity, and emotional disinhibition, which may mimic mania. ¹³ Lupus and small‐vessel ischemic disease can also present with similar psychiatric symptoms when inflammation or ischemia impacts the same brain regions. ¹⁴ , ¹⁵

Perimenopause alters the hormonal and immune atmosphere in the brain, heightening vulnerability to the effects of inflammation. Both estrogen and dehydroepiandrosterone sulfate decline during this transition. This results in increased production of pro‐inflammatory cytokines, including interleukin‐1 (IL‐1), IL‐6, and tumor necrosis factor‐alpha (TNF‐α), with a corresponding drop in CD4⁺ T cells and B cells. ⁹

It is important to note that this patient's clinical record did not include direct measurement of inflammatory markers (IL‐1, IL‐6, and TNF‐α) or gonadotropin levels (FSH, LH). The mechanistic discussion represents a pathophysiologic hypothesis informed by the MS and perimenopause literature, rather than direct biomarker evidence from this individual. The inflammatory basis of mania itself remains inconsistently supported across studies and should be regarded as an area of active inquiry rather than an established mechanism.

We hypothesize that the perimenopausal immune shift may have contributed to a lower neuropsychiatric threshold for expression of her underlying MS. The temporal coincidence of her first manic episode with the onset of perimenopausal symptoms is offered as a clinically suggestive pattern warranting investigation, not a mechanistic conclusion.

TREATMENT IMPLICATIONS

Distinguishing between primary bipolar disorder and secondary mania results in major alterations in treatment algorithms. Ms. S only achieved partial stabilization with antipsychotics and lithium, which prompted further questioning of the presumed diagnosis, as the temporary symptom control did not reveal or address the underlying disease process. The 2018 Canadian Network for Mood and Anxiety Treatments and International Society for Bipolar Disorders (CANMAT/ISBD) guidelines recommend that assessment of suspected bipolar disorder in older adults include neuroimaging, particularly when there are focal neurological signs, abrupt late onset, or a presentation that differs from previous episodes. ¹⁶

A 2023 update to these guidelines affirms that late‐onset bipolar disorder is often related to neurological or physical comorbidities. ¹⁷ Other major guidelines offer similar recommendations. The United States Department of Veterans Affairs/Department of Defense (VA/DoD) guidelines for the management of bipolar disorder (2023) recommend that neuroimaging be done for patients with abnormal findings on history or neurological exam, like our patient's leg weakness. ¹⁸ As reviewed in the American Family Physician journal, it is recommended to perform an electroencephalogram (EEG), MRI (preferred), or computed tomography (CT) in patients with new‐onset psychosis to rule out secondary causes. ¹⁹

LIMITATIONS

This report describes a single patient, and its conclusions cannot be generalized to all cases of late‐onset mania. The retrospective nature of the case limits what we can say with certainty about how perimenopause and neurological disease interacted in real time. The sequence of psychiatric, neurological, and radiologic findings could suggest diagnostic anchoring occurred, but we also recognize the impact of hindsight bias. The presentation was likely more complex than it appeared at each stage of her care.

CONCLUSION

Although emerging literature has identified first‐onset mania during the perimenopausal transition, new‐onset mania in midlife remains atypical and should prompt careful evaluation for secondary medical and neurologic causes. In cases of mania presenting after age 40, clinicians should consider brain MRI and autoimmune and inflammatory panels. Radiology reports do not always account for the full clinical picture; including specific clinical concerns in the imaging order can meaningfully improve diagnostic accuracy, as illustrated by the initial MRI in this case. As our understanding of the intersection among inflammation, autoimmunity, vascular insults, and neuropsychiatric symptoms advances, the workup for late‐onset mania should be standardized to account for these factors, as patients' lives may depend on an accurate diagnosis. Identifying contributors beyond primary bipolar disorder and hormonal changes can prevent unnecessary psychiatric labeling, allow for early targeted treatment, and honor the complexity of the brain–body connection.

AUTHOR CONTRIBUTIONS

Zaid Nathani: Conceptualization; investigation; literature review; writing—original draft; writing—review and editing. Helene Alphonso: Conceptualization; investigation; clinical care of the patient; literature review; supervision; writing—original draft; writing—review and editing. All authors have read and approved the final version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS APPROVAL STATEMENT

This is a retrospective single‐case clinical report involving a deceased individual. As such, the work did not constitute human subjects research and was not subject to Institutional Review Board approval at the participating institutions. The work was conducted in accordance with the principles of the Declaration of Helsinki.

PATIENT CONSENT STATEMENT

The patient described in this case is deceased. Written informed consent for publication was therefore not feasible. To protect patient confidentiality, non‐essential identifying details (including age and ethnicity) have been altered or omitted; clinical events, diagnostic findings, and treatment course are reported as they actually occurred. This case is reported in accordance with the Committee on Publication Ethics (COPE) guidelines for case reports involving deceased individuals.

CLINICAL TRIAL REGISTRATION

Not applicable.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.