Transthyretin leptomeningeal amyloidosis

Hereditary transthyretin leptomeningeal amyloidosis (hATTR) is a rare disorder that may mimic neoplastic, infectious and inflammatory meningeal diseases. The combination of diffuse leptomeningeal enhancement on magnetic resonance imaging (MRI) with disproportionately elevated CSF protein is characteristic. Definitive diagnosis requires genetic testing. A 52-year-old man presented to the neurology clinic with a 1-year history of progressive headache, memory impairment, slowed responsiveness, and difficulty with stair climbing and standing from a seated position. Headache severity was rated 5 on the Visual Analogue Scale (VAS). Cognitive assessment revealed a Mini-Mental State Examination score of 15 and a Montreal Cognitive Assessment score of 8, indicating significant cognitive dysfunction relative to his middle school education level. Physical examination demonstrated bilateral positive Babinski signs, neck stiffness and a positive Kernig sign. Muscle strength graded by the Medical Research Council (MRC) scale was 4/5 in the lower limbs and distal upper limbs, and 5/5 in the proximal upper limbs. Lumbar puncture showed an opening pressure of 55 mmH2O. Cerebrospinal fluid (CSF) analysis revealed a cell count of 2.0 × 106/l, markedly elevated total protein (4133.6 mg/dl), decreased chloride (110.9 mmol/l), and reduced glucose (3.4 mmol/l). CSF studies were negative for infectious and neoplastic etiologies. Nerve conduction studies and needle electromyography were unremarkable except for the absence of H-reflexes. MRI of the brain and spine demonstrated diffuse linear enhancement with thickening of the cerebrospinal leptomeninges, skull base, spinal cord parenchyma and nerve roots (Figure 1A and B, red arrow). A dura biopsy at the T11-L1 level revealed gray-white fibrous tubular structures (Figure 1C, black arrow), with Congo red staining (Figure 1D) under polarized light showing characteristic apple-green birefringence (Figure 1E, red arrow), consistent with leptomeningeal amyloidosis. Genetic testing identified a heterozygous variant in the transthyretin (TTR) gene (NM_000371.4, c.133G>A, p. Ala45Thr), confirming the diagnosis of hereditary transthyretin leptomeningeal amyloidosis (hATTR). After 3 months of treatment with tafamidis 20 mg daily, the patient’s headache VAS score decreased to 1, but limb weakness and cognitive deficits persisted. (A) Contrast magnetic resonance imaging (MRI) of the brain revealed extensive linear leptomeningeal enhancement (arrows); (B) Contrast MRI showed multiple patchy intramedullary enhancements in the cervicothoracic spinal cord and meninges (arrows). (C) Spinal meningeal biopsy of T11-L1 showed multiple gray-white flocculent deposits and hyperplasia (arrow). (D) Histopathological examination of the biopsy specimens revealed amorphous brick-red material on Congo red staining. (E) Apple-green birefringence under polarized light microscopy (arrows). hATTR is an autosomal dominant disorder caused by mutations in the TTR gene, leading to the dissociation, misfolding and aggregation of transthyretin protein into amyloid fibrils that deposit in various tissues.1 While cardiac amyloidosis and transthyretin amyloid polyneuropathy are the most common clinical manifestations, leptomeningeal involvement is rare and often underrecognized.2 Radiological features of TTR-associated leptomeningeal amyloidosis include homogeneous, extensive leptomeningeal enhancement with nerve root infiltration, necessitating differentiation from neoplastic, infectious and inflammatory etiologies. Neoplastic disorders such as primary diffuse leptomeningeal gliomatosis, primary meningeal melanomatosis or leptomeningeal carcinomatosis secondary to extensive dissemination of other malignancies.3 Infectious etiologies such as tuberculous meningitis or viral meningoencephalitis. Inflammatory and autoimmune disorders, such as rheumatoid meningitis, neurosarcoidosis, primary central nervous system vasculitis or IgG4-related disease.4 Definitive hATTR diagnosis relies on tissue biopsy with histopathological confirmation of amyloid deposits, supported by Congo red staining and genetic testing. Notably, biopsy positivity rates vary by site: salivary glands (91%), peripheral nerves (80%) and cardiac tissue (∼100%) yield higher detection rates compared to skin (70%) or subcutaneous fat (14-83%).5 This case highlights the critical role of contrast-enhanced MRI in identifying leptomeningeal amyloidosis and the necessity of genetic testing for hATTR confirmation, particularly in absence of classic systemic features. While disease-modifying therapies like tafamidis are currently considered ineffective for leptomeningeal amyloidosis,6 this patient experienced marked headache relief despite unchanged neurological deficits. This study was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. We thank the patients and their families for their participation in this study. Yusen Qiu (Investigation [lead], Project administration [lead], Writing—review & editing [lead]), Dandan Tan (Project administration [equal], Writing—original draft [equal]), Min Zhu (Data curation [equal], Writing—original draft [equal]), and Daojun Hong (Investigation [equal], Writing—review & editing [equal]) Conflict of interest: None declared. This work was supported by the National Natural Science Foundation of China (82401687 and 82271439).

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