Developmental regression and neurodegeneration — formative SAQs

Question 1 (10 marks)

A previously well fourteen-year-old girl is brought to the emergency department after ten days of insomnia, agitation, and visual hallucinations, followed by a generalised tonic-clonic seizure. On examination she is intermittently distractible, has repetitive orofacial chewing movements, and her conscious level fluctuates. Basic bloods, a first brain MRI, and a routine waking EEG are unrevealing. [3] [4]

(a) Define developmental regression and explain why this presentation is a neurological emergency rather than a primary psychiatric disorder. (3 marks) [3]

(b) Give the most likely diagnosis and outline the clinical framework that justifies acting before the antibody result returns. (4 marks) [3] [4]

(c) Describe the immediate management, including the first-line treatment and the investigations sent in parallel. (3 marks) [4]

Model answer

Developmental regression is the loss of previously acquired milestones, distinguished from delay, plateau, and a static deficit by a trajectory that was demonstrably higher six months ago than today. This presentation is a neurological emergency because the combination of subacute psychiatric onset, seizures, a movement disorder, and a fluctuating conscious level is the phenotype of autoimmune encephalitis, a disorder that is fully reversible with early immunotherapy and worsens - sometimes irreversibly - with delay. Dismissing it as a primary psychiatric disorder in its early phase is the cardinal error, because the window for recovery is measured in days to weeks. [3]

The most likely diagnosis is anti-NMDA-receptor antibody encephalitis. The Graus diagnostic framework permits a diagnosis of probable autoimmune encephalitis on the clinical phenotype - subacute onset of at least three of psychiatric symptoms, seizures, a movement disorder, autonomic instability, and a decreased level of consciousness - supported by an abnormal EEG, CSF, or brain MRI, before the cell-based antibody panel confirms it. The framework exists precisely so that empirical immunotherapy is justified before the result returns, because the panel can take weeks and the outcome is better the earlier treatment begins. [3] [4]

The immediate management is urgent paediatric neurology and neuroimmunology referral with first-line immunotherapy - high-dose methylprednisolone combined with intravenous immunoglobulin or plasma exchange - while sending CSF and serum for the autoimmune encephalitis panel, screening for an ovarian teratoma in an adolescent girl, and providing supportive care for seizures, dysautonomia, and airway protection. A poor early response is the signal to escalate to second-line therapy with rituximab or cyclophosphamide. [4]

Question 2 (10 marks)

An eighteen-month-old girl developed normally for the first year but over three months has stopped using the few words she had, lost purposeful hand use, and begun repetitive midline hand-wringing movements. Her gait is wide-based and unsteady, and her head circumference has crossed two centiles downward. Separately, a six-year-old boy has lost the ability to understand spoken language over four months and has a normal waking EEG. [2] [5]

(a) Give the most likely diagnosis for the girl and the diagnostic test, naming two clinical features from the history that establish the diagnosis. (4 marks) [2]

(b) Give the most likely diagnosis for the boy and the single investigation that is most likely to reveal it, explaining why the initial trace was normal. (3 marks) [5]

(c) State the unifying principle that governs the investigation of any child with developmental regression, and name the single highest-yield genetic test when targeted testing is unrevealing. (3 marks) [1]

Model answer

The girl has Rett syndrome. The diagnosis is established clinically by a period of normal early development followed by regression with loss of purposeful hand use and the emergence of characteristic midline hand stereotypies (wringing, washing, clapping), alongside gait dyspraxia and deceleration of head growth, and it is confirmed by molecular testing of MECP2. The revised 2010 diagnostic criteria anchor the diagnosis on the regression with loss of purposeful hand skills and the stereotypies. [2]

The boy has Landau-Kleffner syndrome, a treatable epileptic encephalopathy presenting with acquired verbal auditory agnosia and loss of language in a child aged three to eight, with seizures and epileptiform activity on EEG. The single most revealing investigation is an electroencephalogram that includes sleep, because the epileptiform abnormalities of Landau-Kleffner syndrome, which may be absent or sparse in wakefulness, are markedly activated during sleep - which is why a routine waking trace was reported as normal. The wider syndrome of continuous spikes and waves during slow sleep shows electrical status epilepticus of sleep. [5]

The unifying principle is that developmental regression is a red-flag presentation that mandates a search for a progressive - and potentially treatable - cause, and that no child should be labelled degenerative or palliative until the treatable causes have been actively excluded. When targeted assays, imaging, and EEG are unrevealing, the single highest-yield genetic test for unexplained neuroregression is trio exome or genome sequencing, analysing the child and both parents together. [1]