Bipolar Disorder in Patients With Tuberous Sclerosis Complex: Causation or Correlation?

Tuberous sclerosis complex (TSC) is a neurocutaneous disease that affects multiple organ systems, primarily manifested as widespread hamartomas in the brain, kidneys, eyes, skin, heart, and lungs (1). It is an autosomal dominant genetic syndrome; TSC1 and TSC2 are the culprit genes in all cases, encoding hamartin and tuberin, respectively (2). The incidence of TSC is reportedly 1 in 6,000 births, affecting all ethnicities and races equally, with widely variable presentations (3). Diagnostic criteria are based on genetic testing and clinical signs and symptoms. A positive screening for either gene alone qualifies as a diagnosis. A negative result, however, does not rule out the disease. A definitive clinical diagnosis is made with at least two major features or one major and two minor features (3). Table 1 lists clinical criteria for TSC from recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference (4).

Cortical tubers are observed in approximately 90% of TSC patients, are a type of focal cortical dysplasia, and frequently serve as epileptogenic nidi (5). Neuropsychiatric disorders are commonly associated with TSC, including autism in 25%–50% and anxiety disorders in 30%–60% of TSC patients (6). Psychosis is seen among patients with TSC, but the concurrence rate is no greater than the incidence of psychosis in the general population (7, 8). The association of TSC with bipolar disorder (BD) is less well documented (9). The following case report describes an individual with a history of TSC and newly diagnosed BD. A literature review of cases of co-occurring TSC and BD is the basis for a discussion of potential explanations for the dual diagnosis. These explanations include genetic linkage between TSC and BD and a structural theory, by which cortical tubers directly lead to neuropsychiatric changes in BD.

Case Report

A 40-year-old female, with a medical history of TSC, presented to the emergency department with 2 weeks of worsening altered mental status, which had escalated over the previous 4 days. She presented with aggressiveness, combativeness, confusion, and psychotic features. Psychotic symptoms included delusions and disorganized behavior, such as believing that the hospital was a trap and that her mask was sprayed with something, telling other patients to remove their masks or leave, and demanding that her daughter take a pregnancy test for no reason. No hallucinations were reported. The patient and her husband endorsed positive signs and symptoms of mania in the patient over the previous 2 weeks, including decreased sleep, increased talkativeness, flight of ideas, increased energy, indiscreet behavior, and increased activity level. She also presented routine paperwork for a recent doctor’s appointment, in which the forms were filled with erroneous and superfluous answers, consistent with hypergraphia. Similar but less intense behavior had been ongoing for an unspecified number of years, occurring once a month to every few months, but this was the only episode severe enough to require hospitalization because of acute safety risks to others.

At age 17, the patient was diagnosed as having TSC; she experienced seizures, a subependymal giant cell astrocytoma (status after resection in 1997), and an angiomyolipoma (status after partial left nephrectomy in 2010). She had no family history of bipolar disorder or schizophrenia. She denied any illicit drug use but endorsed infrequent alcohol and vaporized nicotine use. Laboratory results, including electrolytes, urinalysis, urine drug screen, thyroid studies, complete blood count, ethanol level, COVID screening test, urine pregnancy test, HIV, hepatitis panel, rapid plasma reagin test, vitamin B12, folate, hemoglobin A1c, and lipid panel, were within normal limits. A CT scan of the head showed an unchanged hypodensity in the left posterosuperior frontal lobe, consistent with a cortical tuber, and an MRI brain scan and CT abdomen scan demonstrated stigmata of TSC but no acute abnormalities. Differential diagnosis included a primary psychotic disorder and bipolar I disorder, which seemed more likely, given her presenting manic episode and history of similar episodes.

Lithium 300 mg orally two times daily was initiated for presumed BD with psychotic features. After 1 day of treatment, she became less combative and irritable. However, her renal function declined, and the lithium trial was discontinued on day 2. Intravenous fluid maintenance was started, and renal function normalized.

On day 4, she started divalproex-EC 500 mg administered orally twice daily and aripiprazole 10 mg administered orally once daily, with the goal of eventually utilizing divalproex-EC as monotherapy. On day 5, the patient reported her mood returning to baseline, confirmed improved sleep, and denied any paranoid ideation or manic symptoms. Aripiprazole was discontinued by day 6, and divalproex-EC was decreased to 750 mg administered once daily because of a mildly elevated blood level.

On day 8, the patient was deemed stable, based on normalization of sleep and mood and resolution of psychosis. She was discharged on divalproex-EC 750 mg with a valproic acid level of 128 mcg/mL, close to the desired therapeutic range of 50–125 mcg/mL for mania. Her psychiatric diagnosis throughout the admission remained BD with psychotic features, most recent episode manic.

Discussion

TSC is strongly associated with epilepsy, autism, intellectual disability, and hyperactivity (9). Our literature review revealed only five other case reports of comorbid TSC and BD (9–13). Of these, only Chopra et al. (9) and Ulukök et al. (10) reported BD with psychotic features in a patient with TSC, as we report here. The classic cortical tubers in TSC, as well as microscopic structural changes to neurons within the pathological growth, have been directly linked to epilepsy, and may be linked to neuropsychiatric conditions, such as autism and intellectual disability (5, 7, 14, 15). Satzer and Bond (16) provide evidence illustrating effects of brain lesions on mood changes, such as mania in patients with BD, further supporting this structural theory (10, 17). In our case, neuroimaging demonstrated multiple lesions attributed to TSC in the patient’s brain, concentrated in the posterior superior frontal lobe, where structural and volumetric changes are known to be associated with mood disturbances, such as major depressive disorder (18). The lack of literature and limited available medical history, including the nature and timeline of possible past manic or hypomanic episodes, rendered us unable to determine whether her BD was secondary to a known previous medical condition (TSC) or whether it was a primary psychiatric condition comorbid with TSC.

Genetic studies have revealed linkage between TSC gene loci and genes implicated in BD (19). Specifically, the TSC2 gene is located in chromosomal region 16p13.3, which is in the vicinity of CREBBP, which is a BD risk gene, and PDPK1, which is involved in tumor growth and possibly suicidality (20, 21). Research could investigate the potential importance of the proximity of these genes, the possible role of TSC in the later development of BD, or other common etiologies of these conditions.

Our case elucidates important points about the treatment of BD in patients with TSC. Our patient’s mood began to stabilize following 1 day of lithium treatment. It is unusual that lithium would affect the course of illness so rapidly, and thus her improvement was likely related to the natural course of her manic episode. She remained in the hospital for several days, as her mood fully stabilized and as maintenance treatment for her BD was established. The combination of lithium’s potential nephrotoxic effects and her history of renal tubers and partial nephrectomy likely contributed to increased creatinine and a decreased glomerular filtration rate following lithium initiation. Many patients with TSC have renal damage from disease or surgical intervention and so may be similarly unable to tolerate lithium, a first-line treatment for BD (3). These patients may tolerate treatment with other first-line agents, such as divalproex and second-generation antipsychotics, as did our patient.

Conclusions

TSC is strongly linked to neurocognitive disorders, but it is also important to screen for and treat comorbid mood disorders, such as BD. Explanations for the association between TSC and BD include structural pathology, genetic linkage, and chance concomitant association. Future genetic research may elucidate potential shared genetic components, which could become an additional explanation of this phenomenon. Managing BD involves the use of standard psychotropic medicines while keeping in mind potential renal insufficiency in TSC.

Key Points/Clinical Pearls