Neuropsychiatric manifestations of tuberous sclerosis in a young man in a psychiatric hospital in Botswana: a case report

Introduction

Tuberous sclerosis complex (TSC) is a multisystem disorder; documentation of its characteristic facial skin lesions date back to the 19th century. ¹ A detailed description of its neurological symptoms and gross pathology in the central nervous system was first provided by Bourneville in 1880. ¹ Further clinical descriptions of this disorder have followed over the years, and Moolten first used the term “tuberous sclerosis complex” in 1942. ² More recent literature has reported the different organ systems affected by the disorder as well as key scientific developments, which have led to our current knowledge of the genetics and molecular mechanisms of TSC.^2,3

Inheritance of TSC follows an autosomal dominant Mendelian pattern. Mutations in the TSC1 or TSC2 gene have been identified as the cause of TSC. ⁴ These mutations lead to the dysregulation of the mammalian target of rapamycin (mTOR) signaling cascade, which is responsible for cell proliferation. Mutations in TSC genes result in cascade hyperactivation by decreasing downstream inhibition of the mTOR complex, which leads to abnormal cell proliferation, thus forming hamartomas.^4,5 The development of hamartomas affects a wide range of bodily organs, hence the multisystem involvement. ⁴ Although other manifestations of the disease (especially neuropsychiatric symptoms) are not directly linked to the formation of hamartomas, they are also believed to be a consequence of abnormal signaling of the mTOR pathway. ⁵

Skin manifestations are the most prevalent finding in patients with TSC; the most common are ash-leaf lesions (hypopigmented lesions most frequently observed on the trunk and gluteal regions). Other lesions, such as angiofibroma, café-au-lait spots, confetti-like macules, periungual fibromas, forehead plaques, and shagreen patches, are also prevalent. ⁶ Other affected organ systems include the heart, kidneys, lungs, teeth, and eyes. The possible symptoms of TSC in different organ systems are represented in the diagnostic criteria for this disorder. ⁷ Although skin lesions are the most prevalent findings, it is important to note that central nervous system involvement is the most common finding that leads to morbidity and mortality. ⁸

The Neuropsychiatry Panel of the 2012 International Consensus Conference for TSC coined the term “TSC-associated neuropsychiatric disorders” (TAND) to represent various neuropsychiatric symptoms across distinct levels (behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial), thus creating a standardized language to communicate this umbrella of manifestations. The clarification of these dimensions helped to clarify the possible neuropsychiatric complications of TSC. A TAND checklist to further aid assessment is also now available. ⁸

Symptoms at the behavioral level encompass observed behaviors that are of concern to the clinician, patient, and caregivers, such as anxiety, mood changes, or aggressive behaviors. Psychiatric manifestations include any psychiatric disorders defined by the Diagnostic and Statistical Manual of Mental Disorder or International Classification of Disease. Intellectual ability and academic functioning (e.g., learning disorders) are another dimension that require assessment and monitoring. The psychosocial functioning of each individual also needs to be assessed regularly because related disorders can affect the self-esteem of patients or result in family difficulties.^8,9

As a rare disorder—estimated to affect 1 in 6000 to 1 in 10,000 people globally ⁴ —TSC is not well studied in low-resource settings. We therefore present the neuropsychiatric findings from a known epileptic patient who was referred to a psychiatric hospital with post-ictal confusion and psychotic symptoms, and who was later diagnosed with TSC. The reporting of this case study conforms to CARE guidelines (for CAse REports). ¹⁰

Case report

We report the case of a man in his mid-20s who presented to our outpatient department at Botswana’s only referral-accepting psychiatric hospital. According to the patient’s father, he had a 1-day history of confusion, abnormal behavior, aggression, and talking nonsensically. Previous to this, a seizure was witnessed at home 1 week earlier by his father, whose description was suggestive of a generalized tonic–clonic seizure.

The abnormal behavior as reported by the patient was that he grabbed a cat by its tail as it was trying to climb on top of a highly esteemed religious leader's photo in the living room. He reported that he got poisoned by the cat when it scratched him with its claws. Since this incident, he had become suspicious of others in his home and became aggressive. The patient’s father corroborated a history of unprovoked aggressive behavior (both physical and verbal) but did not know about the cat incident. Other psychotic symptoms were not present and a review of psychiatric domains, such as mood and anxiety, were normal.

The patient had been diagnosed with generalized epilepsy at the age of 12 and was managed at a primary health-care level. In retrospect, this may have been an error, because patients with TSC typically have focal epilepsies that are usually identified relatively early in life. Over the years, the patient’s epilepsy remained uncontrolled despite reported good adherence to three antiseizure medications (carbamazepine 400 mg daily, sodium valproate 2 g daily, and phenobarbitone 60 mg daily). He reportedly had breakthrough seizures every 2 weeks. Because of the unavailability of therapeutic drug monitoring, this was unfortunately not performed. However, investigations such as a full blood count, renal and liver function tests, and a urine toxicology screen revealed normal results. At the time of writing, the patient takes sodium valproate and phenobarbitone. He had no other medical comorbidities and had sober habits.

The genogram in Figure 1 represents family members with reported skin lesions. Family members also had varying levels of intellectual disability, and most had epilepsy. The patient’s uncle was reported to have autism-like features, and the patient’s aunt and sister, who is blind, had undisclosed mental illness. Moreover, a younger sibling died during infancy, although the cause remains unknown.

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Figure 1.

Genogram representing similar skin lesions in the patient’s family members.

A physical examination revealed angiofibromas on the patient’s cheeks, fibrous plaques lateral to the left eye, and hypomelanotic lesions on the chin (Figure 2). A neurological examination was performed 5 days after admission and demonstrated dysdiadochokinesia, dysmetria on finger-to-nose testing, and an intentional tremor, which are consistent with cerebellar dysfunction. No ataxia was noted, and the rest of the neurological examination and other organ systems were unremarkable.

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Figure 2.

Neurocutaneous manifestations of tuberous sclerosis complex in the patient: angiofibromas on the cheeks, fibrous plaques lateral to the left eye, and hypomelanotic lesions on the chin.

On the initial mental state examination, the patient was drowsy and had slurred speech. The rest of the mental state examination was therefore deferred to a later stage. On follow-up, 2 days after admission, the patient was calm and cooperative. However, there was significant speech latency and the patient used vulgar language. He also had persecutory delusions, believing his family wanted to poison him, and overvalued religious ideas were noted. He did not have any perceptual disturbances, but displayed poor judgment and insight. The Mini-Mental State Examination score was 18 out of 30, with points lost in attention, calculation, sentence construction, and orientation.

A multidisciplinary team managed the patient during his admission. The team consisted of a psychiatrist, doctors, nurses, an occupational therapist, and a social worker. Given the high burden of disability in the patient’s family, the social worker ensured that they were receiving support from social services. During admission, the patient had only one generalized-onset seizure, which was stopped with diazepam. Brain magnetic resonance imaging (MRI) and a genetic panel were performed; the findings were in keeping with TSC, including the identification of diffuse cortical and sub-cortical tubers, subependymal nodules, and radial bands on MRI (Figure 3), as well as a TSC2 gene mutation. An abdominal ultrasound excluded renal pathology, and an echocardiogram was also normal.

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Figure 3.

Magnetic resonance imaging highlighting subependymal hamartomas (a), cortical and subcortical tubers (b), and radial bands (c).

Psychoeducation and genetic counselling were provided and continued with subsequent follow-ups. It is worth noting that the family had attributed the disorder to witchcraft, which reinforces the importance of diagnosing genetic conditions in our setting. The implications of the condition on reproductive outcomes were explained, highlighting that there is at least a 50% risk of having a child with TSC if you have the condition.

On outpatient follow-up it was discovered that the patient had mild to moderate intellectual disability with impairment in the practical and social domains, as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This assessment was made after the patient’s psychosis had resolved. The TAND checklist was completed at this time. Concerns with social interaction were noted, as well as difficulties with most specific cognitive skills including attention, multi-tasking, visuospatial tasks, and executive skills. One month after his initial presentation, the patient remains stable with good seizure control using sodium valproate and phenobarbitone. This improvement may be attributed to stopping carbamazepine use because the concomitant administration of carbamazepine, which has enzyme-inducing properties, reduces serum sodium valproate levels.

Discussion

Originally developed in 2012, the International TSC Clinical Consensus Group released updated guidelines for the diagnosis of TSC in 2021. ¹¹ Our patient had four major features: hypomelanotic macules, angiofibroma, multiple cortical tubers, and subependymal nodules.

A TSC2 mutation was confirmed in this patient through genetic testing, which detected a pathogenic variant. It is worth noting that a positive genetic test is enough to diagnose TSC, even without major or minor features. ¹¹ However, a negative genetic test does not rule out TSC because pathogenic TSC mutations remain undetected in 10% to 15% of cases, likely because some mutations that are responsible for the condition remain unknown.^4,11 A thorough clinical assessment and investigations are therefore essential.

It is worth noting that infantile spasms are frequently observed in individuals with TSC who are also diagnosed with epilepsy.^11,12 Many patients with infantile spasms progress to develop Lennox–Gastaut syndrome. ¹³ Earlier-onset infantile spasms are associated with poorer neurodevelopmental and cognitive outcomes. ¹¹ The present patient was diagnosed with epilepsy at 12 years of age; however, it was unclear whether he had any other early manifestations of TSC. A multicenter, international study of TSC patients in 31 countries revealed that, in most cases (79% of patients), epilepsy was diagnosed before 2 years of age, and that infantile spams were more commonly associated with TSC2 mutations than with TSC1 mutations. ¹⁴

In a systematic review of the prevalence and clinical and neuropathological characteristics of patients with cerebellar degeneration and epilepsy, patients with temporal lobe epilepsy and uncontrolled epilepsy were found to have a higher prevalence of cerebellar degeneration. ¹⁵ Moreover, the antiseizure medications most associated with neuropathological cerebellar changes included phenytoin, phenobarbitone, and carbamazepine. The cerebellar signs exhibited by our patient may therefore be a direct manifestation of uncontrolled epilepsy, or of the use of phenobarbitone and carbamazepine, or both. Although it did not occur with our patient, primary care physicians should promptly refer patients with uncontrolled epilepsy to specialized care.

A wide range of psychiatric symptoms have been reported in the literature among patients with TSC. The most commonly reported are autism spectrum disorder and intellectual disability, followed by depressive and anxiety disorders.^16,17 TSC2 mutations are reportedly associated with a more severe course of neuropsychiatric manifestations. ¹⁸ According to De Vries et al., TSC2 mutations have a stronger association with autism spectrum disorder and intellectual disability than TSC1 mutations. ¹⁶ Our patient presented with psychotic symptoms and was assessed as having below-normal intelligence. His family members with similar skin lesions were also reported to have intellectual difficulties, and one had autism-like features. The presence of these symptoms can impact psychosocial functioning in individuals with the disorder. ⁹ Notably, psychotic symptoms are not commonly observed on their own, but are often linked to seizures, ⁹ similar to the post-ictal psychosis experienced by our patient.

The importance of neuroimaging in TSC goes beyond aiding in diagnosis; it is also important for assessing the full extent of neurological involvement. Imaging is therefore an important aspect of treatment planning. Common findings include cortical tubers, subependymal nodules, subependymal giant cell astrocytomas, and white matter abnormalities. ¹⁹ Cortical tubers are detectable in around 95% of patients with TSC, and are associated with the development of epilepsy, intellectual disability, and behavioral difficulties. ¹⁹ Subependymal nodules are also a common finding; they can degenerate into subependymal giant cell astrocytomas, which tend to grow slowly and have a better prognosis. ¹⁹ Our patient had diffuse cortical and sub-cortical tubers with subependymal nodules. The presence of radial bands, which are specific for TSC, was also detected on MRI. No subependymal giant cell astrocytomas were identified. His Mini-Mental State Examination was 18, suggesting that his cognitive impairment may have been the direct result of cortical tubers or uncontrolled epilepsy.

In low-resource settings, the challenges associated with TSC management include poor access to MRI, a lack of genetic testing, and the unavailability of mTOR pathway inhibitors.^20,21 In South Africa, an expert panel endorsed the international guidelines and made further recommendations for managing patients in the South African context. Some of their resolutions included establishing a South African registry for TSC patients, advancing research in the area, and providing access to mTOR inhibitor treatments. In Botswana, genetic testing for TSC is currently unavailable, and management is primarily focused on symptom control. In the present case, the patient’s genetic testing was performed in South Africa after special arrangements were made.

The Neuropsychiatry Panel at the 2012 TSC International Consensus Conference recommended the annual screening of neuropsychiatric symptoms for all TSC patients, because these symptoms represent the greatest burden of the disease. ¹⁰ A TAND checklist was thus developed to comprehensively monitor neuropsychiatric symptoms at all levels. The creation of this checklist aimed to lead to the earlier identification of problems; once identified, psychosocial and pharmacological management can be initiated. ⁸

Management strategies may involve the implementation of early intervention methods, development of individual education plans, provision of special education services, and/or establishment of academic, social, and vocational support. These strategies are essential for individuals with autism spectrum disorder, attention deficit hyperactivity disorder, and intellectual disability. ⁹ Furthermore, evidence supports the use of mTOR inhibitors to treat renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, and facial angiofibromas. ²² However, more studies are needed to evaluate their specific utility for managing neuropsychiatric manifestations. In Botswana, there is no access to these drugs because of limited resources.

We have identified some key areas in which the management of our patient may have been improved. For example, there was a delay in diagnosing TSC despite symptoms being present during adolescence. This delay meant that some issues (such as intellectual disability) were not identified and managed earlier by a multidisciplinary team. This was coupled with inadequate management of the patient’s uncontrolled epilepsy; as a result, his psychosocial and cognitive functioning continued to deteriorate. Additionally, limited resources made it challenging to follow the recommended TAND checklist.

Conclusion

The present case emphasizes the importance of both conducting thorough physical examinations and having knowledge of neuropsychiatric conditions when treating similar patients. The presence of dermatological manifestations coupled with a history of epilepsy should have expedited a diagnosis of TSC in our case. It is also imperative that due diligence is performed to exclude medical causes of altered mental status before a referral to psychiatry. Given that TSC is a rare condition that is often understudied in low- to middle-income settings, it is fundamental to report cases such as the present one, to raise awareness of the condition.

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