|Year : 2023 | Volume
| Issue : 1 | Page : 2-6
Tuberous sclerosis complex presenting as afebrile encephalopathy: Diverse etiology, unitary approach
Prarthana Kharod1, Devendra Mishra2, Deepti Chawla1, Anurag Pandey1, Monica Juneja2
1 Department of Pediatrics, Maulana Azad Medical College, Delhi, India
2 Child Development Center, Maulana Azad Medical College, Delhi, India
|Date of Submission||15-Aug-2022|
|Date of Decision||23-Jan-2023|
|Date of Acceptance||23-Jan-2023|
|Date of Web Publication||27-Feb-2023|
Dr. Anurag Pandey
Department of Pediatrics, Maulana Azad Medical College, Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Background: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with a range of physical manifestations that require regular evaluation, surveillance, and management. Central nervous system manifestations are the major cause of morbidity and mortality in TSC patients. Encephalopathy, which may be due to multiple etiologies, maybe seen sometimes in these patients. Clinical Description: We are sharing a series of three cases, presenting to us within a 6-month period with encephalopathy, who were admitted and treated by us. Etiologies were identified in all three cases with variable spectrum from nonconvulsive status epilepticus to autistic regression to valproate-associated hyperammonemia. Management: All three patients admitted with us were treated as per clinical guidelines for respective etiologies. All patients respond well to treatment and were discharged and are under regular follow-up. Conclusion: There are various etiologies for encephalopathy in a child with TSC. Therefore, thorough history, examination, and investigations should be carried out in every child with TSC to find out the likely cause of encephalopathy, and treatment should be initiated according to the underlying cause.
Keywords: Central nervous system, nonconvulsive status epilepticus, tuberous sclerosis complex-associated neuropsychiatric disorder, tuberous sclerosis complex, valproate-associated hyperammonemic encephalopathies
|How to cite this article:|
Kharod P, Mishra D, Chawla D, Pandey A, Juneja M. Tuberous sclerosis complex presenting as afebrile encephalopathy: Diverse etiology, unitary approach. Indian Pediatr Case Rep 2023;3:2-6
|How to cite this URL:|
Kharod P, Mishra D, Chawla D, Pandey A, Juneja M. Tuberous sclerosis complex presenting as afebrile encephalopathy: Diverse etiology, unitary approach. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Mar 22];3:2-6. Available from: http://www.ipcares.org/text.asp?2023/3/1/2/370528
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that results from mutations in the TSC1 or TSC2 genes on chromosomes 9 and 16, respectively. The estimated population prevalence is 1 in 20,000. It is a protean disease associated with hamartoma formation in multiple organs. The central nervous system (CNS) is commonly affected causing conditions, like intellectual disability (ID), and refractory epilepsy requiring multiple anti-seizure medication (ASMs).,, Lesser known associations are TSC-associated neuropsychiatric disorder (TAND) and encephalopathy, i.e., temporary or permanent conditions affecting the brain's structure or function., This differs from acute encephalopathy which is defined as impaired consciousness with or without other neurologic findings such as seizures lasting for more than 24 h. Multiple differential diagnoses can be considered in the latter [Table 1]. A case series describing acute encephalopathy in TSC reported febrile status epilepticus (SE) as a common cause of acute encephalopathy.
We, herein, describe three children with TSC who presented with acute afebrile encephalopathy due to relatively uncommon causes. Since similar presentations may be encountered by general pediatricians in the emergency room, we detail the noninfectious causes that should be thought of in TSC, and the approach to be used.
| Case 1|| |
A 5-year-old girl presented with a 2-day history of gradually progressive altered behavior; decreased interaction, poor speech, excessive lethargy, reduced oral intake, and cessation of indicating bladder and bowel needs. There was no history suggestive of any focal neurological deficit. There was no concurrent fever, headache, vomiting, seizures, photophobia, neck pain, head injury, exposure to toxins or poisons, upper respiratory tract infection, rashes, or jaundice. The child was a known case of TSC, diagnosed when she manifested with epilepsy at 1 year of age. She had been started on ASM and at present was on daily oral valproate (30 mg/kg/day) and clonazepam (0.06 mg/kg/day). Although her compliance was poor, she had been seizure free for 6 months. The child was under annual follow-up as per standard TSC protocol. Her brain magnetic resonance imaging (MRI) revealed subependymal nodules, and renal ultrasonography showed renal cysts. There was no other significant past history. As per her parents, she was developmentally normal for her age. The family history was not significant.
On examination, the child was hemodynamically stable (respiratory rate 24/min, heart rate 76/min, and normal volume pulses) and maintaining normal saturation under room air. Her anthropometric parameters were normal with a body mass index of 20 kg/m2. A shagreen patch [Figure 1]a and multiple hypomelanotic macules [Figure 1]b were noted on general physical examination. There was no evidence of jaundice, pallor, trauma, petechial, or purpuric rash. The Glasgow coma score (GCS) was 11 (E4V3M4). The cranial nerve examination was unremarkable. Fundus examination, pupillary response, and motor examination were noncontributory. There were no meningeal signs or indicators of increased intracranial tension. Abdominal examination and examination of the cardiovascular system and respiratory systems did not reveal any abnormality.
|Figure 1: (a) Shagreen patch (white arrow) on child lower back and (b) Ash leaf macule (hypopigmented macule) in a patient with Tuberous sclerosis complex|
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Management and outcome
Based on the clinical scenario of nonfebrile encephalopathy in a child with epilepsy (especially in the absence of trauma), the possibilities of nonconvulsive status epilepticus (NCSE), drug toxicity (specifically valproate-related hyperammonemic encephalopathy), acute disseminated encephalomyelitis (ADEM), and autoimmune encephalitis were considered. Initial investigations had already ruled out hypoglycemia, dyselectrolytemia, infection, deranged renal and liver function, and hyperammonia [Table 2]. A lumbar puncture revealed cerebrospinal fluid (CSF) with normal pressure, acellular microscopy, biochemistry within normal limits (sugar 55 mg/100 ml, and protein 32 mg/dl), sterile CSF culture, and negative serology panel for viral meningoencephalitis. Serum valproate levels were normal (64 μg/ml; normal range: 50–100 μg/ml). An urgent electroencephalogram (EEG) showed continuous spikes and waves in the frontal and temporal area, which was suggestive of NCSE. Therefore, we did not proceed with the CSF panel to exclude autoimmune encephalitis.
|Table 2: Diagnostic criteria, comorbid conditions, and initial investigation in three patients with tuberous sclerosis complex|
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The dose of valproate was increased to 40 mg/kg/day and midazolam infusion started. This was escalated to 2 μg/kg/min after shifting the patient to an intensive care setting. The child's clinical condition improved with the attainment of the premorbid level of sensorium and mental status within 72 h of therapy. The repeat EEG was devoid of features of NCSE. The midazolam infusion was gradually weaned off within the next 24 h. She was discharged on valproate (40 mg/kg/day) and clonazepam (0.1 mg/kg/day). The patient has been under regular follow-up now for almost 1 year, has remained compliant, and asymptomatic.
| Case 2|| |
An 11-year-old boy with a diagnosis of TSC was brought with complaints of fever and loose stool for 7 days. The fever was low grade. The stools were frequent, watery, and without blood or mucus. During elicitation of history, it emerged that the child had been exhibiting unusual behavior for the past 1 month. This encompassed progressively increase in ritualistic behaviors, decreasing appetite, intense mood symptoms, decrease in speech output (as compared to before), increased restlessness (unable to sit at one place involved in a favorite activity such as watching TV), aggressive behavior while disobeying parental requests and not responding despite being called repeatedly. There was no self-injurious behaviors. The academic performance had also declined.
There was no history of headache, vomiting, altered consciousness, seizures, neck stiffness with photophobia, paucity, abnormal limb movements or sleep disturbance. On probing, further, we were unable to elicit any history of preceding febrile illness with rashes, gastrointestinal or respiratory symptoms, exposure to chemicals/toxins, head injury, jaundice, dog bite, trauma, bullying at school or substance abuse. The child had been diagnosed with epilepsy at the age of 11 months and was on regular ASM (valproate 30 mg/kg/day). Once TSC had been ascertained, he was managed as per standard protocol. He had also been diagnosed with autism spectrum disorder (ASD) at 4 years (details of evaluation were unavailable) after which he had been started on intervention, but compliance had been irregular for the past 6 years. There was no history of measles or any other significant past illnesses. The child studied in class 4 in an integrated school and was average in studies. There was no history of any other affected family member. He was immunized appropriately for age.
The child was hemodynamically stable, maintaining vitals with preserved anthropometric measurements, and age-appropriate sexual maturity rating. There was no dehydration. Multiple hypomelanotic macules and angiofibromas were present. There was no evidence of local injury, jaundice, petechiae, purpure, rash, or lymphadenopathy. The child displayed severe agitated behavior, but was oriented to time, place, and person; GCS was 14. Pupils were bilaterally of normal size and reaction. There were no focal cranial/neurological deficits or meningeal signs. Rest of the systemic examination was normal and did not provide any clinical indicator for the change in behavior.
Management and outcome
The same differentials of nonfebrile encephalopathy that were considered in the first case were kept, i.e., NCSE, autoimmune encephalitis, and valparin-related hyperammonemic encephalopathy. Initial investigations [Table 2] excluded common metabolic causes. Serum ammonium (30 μg/dl) and lactate (1 mmol/l) levels were within normal range. CSF analysis was normal; acellular, normal sugar (52 mg/dl) and protein (34 mg/dl), and sterile culture. Due to financial constraints CSF was not processed for auto-immune encephalitis, but samples were preserved. The MRI brain showed cortical tubers pathognomic of TSC. There was no leptomeningeal enhancement. The EEG did not reveal any abnormal waves or diffuse slowing of cerebral activity. Over the next 2 days, the fever and loose stools resolved, but the aggressive behavior and decreased interest in surroundings persisted. The alteration in behavior and recent deterioration in social skills were attributed to regression associated with ASD (late regression) that may often occur during puberty or concurrent psychiatric manifestations such as depression. Consultation with a psychiatrist supported the former.
The parents were counseled and actively involved in the management plan. It was decided to treat the child symptomatically; aggression with oral risperidone (1.8 mg/day), clonazepam (5 mg at bedtime), and concurrent intensive behavioral intervention. The child showing gradual decrease in aggression and improvement in social skills in the following 4 months, after which clonazepam was tapered off. The child and family are under regular follow-up for the past year, and he is doing well.
| Case 3|| |
An 8-year-old boy, known patient of TSC with epilepsy (diagnosed since he was 15 months old), presented with new-onset abnormal jerky movements and altered sensorium for a week. The movements were myoclonic in nature and occurred 4–5 times daily. The child was already on valproate (50 mg/kg/day) and levetiracetam (50 mg/kg/day), was compliant, and had been seizure free for the past 4 months. Since the preceding week, the child had also lost interest in surroundings, stopped recognizing his parents, not indicating bladder or bowel movements, was aggressive, and displayed excessive daytime sleepiness. There was no history of fever, headache, vomiting, poor appetite, photophobia, prior vaccination, animal bites, trauma, jaundice, neck stiffness, and drug/toxin exposure. The child was developmentally normal (on history) and studied in class 3 with average academic performance. There was no significant family history.
The child was hemodynamically stable (pulse rate 71/min with regular good volume pulses and respiratory rate of 22/min). The only salient findings on general physical examination, were hypomelanotic macules and shagreen patches. The child was in altered sensorium with GCS of E3V2M4. Cranial nerves evaluation was normal, with no evidence of papilledema on fundus examination. Intermittent myoclonic jerks were observed during examination. There was no sign of cranial or focal neurological deficits, increased intracranial tension, or meningeal irritation. The remaining systemic examination was normal.
Management and outcome
Possibility of drug toxicity, metabolic derangement, NCSE and TAND were considered. Initial investigations ruled out hypoglycemia, infection, hepatic/renal dysfunction, and metabolic causes. The MRI brain did not show any leptomeningeal enhancement, features of ADEM, or other abnormalities apart from the TSC specific features (cortical tuber with subependymal nodules). The EEG showed diffused generalized slowing without ictal changes, suggestive of metabolic encephalopathy. A possibility of valproate-associated hyperammonemic encephalopathy (VHE) was kept and investigations were planned accordingly. The serum ammonia level was elevated (150 mmol/L; normal: 30–50 mmol/L) as was the serum valproate level (120 μg/ml; normal range: 50–100 μg/ml) that became available after 72 h. Valproate was stopped and an alternative drug (clonazepam) was started. The child's sensorium gradually improved within 48 h and he started to recognize his mother and became bowel/bladder continent. The child was discharged on day 7 of admission with complete resolution of encephalopathy. He has been under follow-up for more than 2 years with good compliance, satisfactory seizure control, and no recurrence of similar symptoms.
| Discussion|| |
The CNS is affected in more than 90% of individuals with TSC. The major pathological lesions in the brain include cortical or subcortical tubers, subependymal nodules, giant cell astrocytomas, and white matter migration lines. Childhood encephalopathy is an uncommon but significant pediatric presentation and is associated with significant morbidity and mortality. There are a large number of conditions that may lead to this presentation [Table 1], and evaluation is usually dependent on clinical clues and sequential.
History of seizures is found in 72%–85% of individuals with TSC. Epilepsy begins in the first 3 years of life in more than 80% cases and was incidentally seen in all three patients. Refractory epilepsy is seen in about 75% cases. A multi-center, cross-sectional study of 36 Egyptian children with TSC (2009–2015) reported that 58.3% developed SE; out of which 61.9% had convulsive status, whereas 19.1% had NCSE. Acute encephalopathy has been reported in TSC with febrile SE presenting with NCSE. In the patient with NCSE in this series, there was no preceding or concurrent triggering febrile illness.
TSC is associated with variety of neuropsychiatric manifestations termed as TAND. These are further classified into six levels: behavioral, psychiatric, neuropsychological, intellectual, academic, and psychosocial. Behavioral manifestations encompass depressed mood, anxiety, self-aggression, temper tantrums, sleep abnormalities, and impulsivity. Psychiatric disorders include ASD (seen in 17%–63% affected individuals), attention deficit hyperactivity disorder, generalized anxiety disorder, major depressive disorder, schizophrenia, and other mental illnesses. Around 40%–50% of individuals with TSC have normal intellectual ability, while the remaining have ID of variable severity. The neuropsychological deficits pertain to attention, memory, and executive function. At the psychosocial level, issues such as family stress and difficulties with self-esteem are often reported. The recent introduction of specific screening tools such as the TAND checklist has highlighted that taken altogether, this entity may affect as high as 90% of patients.
Autism is the most frequent condition in TSC in which regression occurs, mainly in the language and social domains. Other manifestations include behavioral changes such as aggression. Regression can appear early (most common) and also (less frequently) late, during adolescence or early adulthood. These cases are often associated with catatonia. The cause for the encephalopathy resulting in behavior alteration in case 2 was autistic regression confounded with the lack of regular and consistent behavioral therapy. Once risperidone and behavior therapy was started, there was significant improvement.
The third patient had encephalopathy due to VHE, which resolved on the withdrawal of valproate. Valproate is a common ASM used for epilepsy in both children and adults. VHE is a rare entity, characterized by acute onset of impaired consciousness with confusion and lethargy, focal or bilateral neurological features, and increased seizure activity. Patients with VHE may present with varying degrees of cognitive and behavioral dysfunction. It can be life-threatening unless a timely diagnosis is made and valproate discontinued, following which complete recovery usually occurs. VHE is associated with hyperammonemia, but serum valproate levels may be within the therapeutic range or above normal. No relationship has been found between the severity of VHE and parameters such as dosage, serum valproate levels, or level of hyperammonemia. A possibility of VHE should be kept in any child on valproate therapy who develops unexplained encephalopathy, irrespective of the duration of use of the drug or its levels. A high blood ammonia level in the absence of hepatic or renal derangement supports the diagnosis.
In conclusion encephalopathy or brain dysfunction leading to alteration in consciousness and/or behavior in a child with TSC has a wide spectrum of differential diagnoses, especially if associated with fever. The challenge arises when infectious and common metabolic causes are excluded. This case series of afebrile encephalopathy highlights the need for a structured approach, establishing timely diagnosis and initiating appropriate treatment that will result in favorable outcomes.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]