Early-onset Leptomeningeal Manifestation of G47R Hereditary Transthyretin Amyloidosis

A 21-year-old British woman experienced recurrent, self-limited episodes of encephalopathy, motor weakness, speech disturbance and seizures lasting hours to days, over a four-year period. On first presentation in 2016, aged 17, lumbar puncture revealed acellular cerebrospinal fluid with raised protein, prompting a diagnosis of viral encephalitis despite negative viral PCR. Non-contrast brain MRI was normal. She was treated with acyclovir and recovered fully after two weeks. Similar self-limited episodes recurred over the years, all with full recovery without treatment. In January 2019, in the context of one further episode, she was diagnosed with temporal lobe epilepsy and started on levetiracetam. In May 2019, she had another episode. Plain brain CT was suspicious for subarachnoid haemorrhage (figure 1A). Subsequent CT arteriography was negative and MR imaging did not confirm a bleed, but revealed diffuse leptomeningeal enhancement of the brain, cranial nerves and spinal cord after gadolinium injection (figure1B). CSF testing was unremarkable, except for persistently raised protein (1.6g/L). Infectious, vasculitic, paraneoplastic and inflammatory/autoimmune causes were excluded. In December 2019, she developed status epilepticus, necessitating intubation and admission to critical care unit. A subarachnoid haemorrhage was diagnosed. Although her generalised seizures improved, she remained dysphasic and continued to have right-sided focal seizures for several weeks. A previously unavailable family history revealed a diagnosis of hereditary transthyretin amyloidosis (hATTR G47R; figure 2) in a paternal uncle and grandmother, who was of Italian heritage, and testing confirmed our patient carried this mutation (her own father had died of an aneurysmal subarachnoid haemorrhage aged 45). On full systems review, her only other symptoms were cyclical vomiting syndrome associated to menstruation, which started in her twenties, and a tendency towards constipation, which in hindsight might relate to an incipient autonomic neuropathy. She also had a mild postural tremor since her early teens. There were no other sensory or motor symptoms suggesting peripheral neuropathy, but recently she developed paresthesia in her hands. She never presented with postural symptoms, arrhythmias or ocular manifestations. Characteristic findings on cardiac magnetic resonance and echocardiogram, Perugini grade 2 cardiac uptake on 99mTc-DPD scintigraphy, and exclusion of a clonal dyscrasia (by serum free light chain assay and serum/urine electrophoresis) fulfilled non-biopsy criteria for cardiac amyloidosis1. Nerve conduction studies were normal. A presumptive diagnosis of hATTR with leptomeningeal disease was made and a trial of Patisiran (Onpattro®, Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA) and Tafamidis (Vyndaqel®, Pfizer, New York, USA) commenced. Two months after discharge the patient remains stable, but with marked language difficulties and low nonverbal cognitive abilities.