We report a case of transthyretin-related amyloidosis in a patient who presented with intracranial and spinal leptomeningeal enhancement, pial siderosis, and engorged intradural spinal veins. In isolation, differential considerations of these 3 findings are broad. Although leptomeningeal enhancement and pial siderosis have been reported in this condition, this is the first time engorged pial vessels have been described in the MR imaging literature. The combination of all 3 finding may be specific for the diagnosis of leptomeningeal transthyretin–related familial amyloidosis.Keywords
Transthyretin-related hereditary amyloidosis is a form of amyloidosis that presents with pain, paresthesias, muscular weakness, and autonomic dysfunction characterized by systemic deposition of amyloid variants of the transthyretin protein. The diagnosis is established by identifying amyloid deposits in biopsy specimens and identification of a mutation in the transthyretin gene. The disease is uniformly fatal in the absence of liver transplantation, but disease progression can be slowed with drug therapy if diagnosed in the early stages. The combination of meningeal enhancement, pial siderosis, and engorged intradural spinal veins may allow an early neuroradiologic diagnosis.
A 43-year-old man presented with a reported history of severe meningoencephalitis 10 years earlier, which manifested at that time as extremity paresthesias, severe aphasia, profound weakness, and incontinence. This was followed by spontaneous improvement without identification of a causative infectious, inflammatory, or autoimmune etiology. He experienced subsequent transient episodes of aphasia and extremity paresthesias superimposed on a persistent mild gait and cognitive deficits from his initial event. The patient had experienced bowel and bladder dysfunction, with progressive lower extremity fatigue in the 9 months preceding his presentation at our tertiary referral center. There was no other significant medical history or significant medications used.
The patient underwent extensive laboratory workup remarkable only for elevated CSF protein and albumin levels. Imaging with PET/CT showed no abnormal uptake to indicate occult malignancy. 1.5T MR imaging of the brain without and with intravenous gadolinium contrast demonstrated diffuse intracranial leptomeningeal enhancement and superficial siderosis (Fig 1). Additional 1.5T MR imaging of the cervical and thoracic spine without and with intravenous gadolinium contrast was performed and was remarkable for diffuse leptomeningeal enhancement along the spinal cord (Fig 2A, -B). Enlarged and tortuous flow voids, compatible with intradural veins, were noted around the conus and within the cauda equina at the time of a 1.5T MR imaging of the lumbar spine without and with intravenous gadolinium contrast (Fig 2C), which raised suspicion of a dural arteriovenous fistula. This prompted a bolus gadolinium-enhanced 1.5T MRA of the spine, which confirmed the enlarged intradural veins and suggested a prominent vessel that extended to the right L3 neural foramen. However, 2 subsequent complete catheter spinal angiograms showed no evidence of a spinal dural arteriovenous fistula or early draining veins. The enlarged pial veins were not confirmed on the catheter spinal angiogram because the catheter runs were not extended into the venous phase.
Open biopsy of the dura and leptomeninges was performed at L3. Although no gross dural or leptomeningeal abnormality was seen, engorged, but not arterialized, veins were present along the nerves of the cauda equina. At pathology, amorphous material was identified in tissue obtained from both the dura and the arachnoid. When stained with Congo red, the amorphous material showed apple-green birefringence under polarized light (Fig 3), diagnostic of amyloid deposition. Both specimens were diffusely replaced by amyloid. There were no vessels in either specimen. Further analysis with liquid chromatography tandem mass spectometry detected a peptide profile consistent with transthyretin-type amyloid.
Further evaluation including an eye and retinal exam, a cardiac MR imaging, and an electromyogram excluded ocular, cardiac, and peripheral neurologic involvement. Treatment with a liver transplantation was considered but ultimately not recommended due to the patient's severe leptomeningeal involvement and secretion of transthyretin-type amyloid into the CSF via the choroid plexus. Therefore, treatment was initiated with doxycycline and ursodeoxycholic acid.
Four months after initiation of treatment with doxycycline and ursodeoxycholic acid, the patient had made marked subjective improvement, with repeated 1.5T MR imaging of the head without and with intravenous gadolinium contrast, which demonstrated objective improvement in leptomeningeal enhancement. The degree of pial siderosis was unchanged. The status of the intradural veins was indeterminate because a repeated lumbar spine MR imaging or MRA was not obtained.
Transthyretin-related familial amyloid polyneuropathy is a heterogeneous autosomal dominant disease composed of nearly 100 unique mutations in the transthyretin gene.1 Mutations are subcategorized, based on the area of involvement and clinical features, into 3 groups, including neuropathic, oculoleptomeningeal, and cardiac subtypes.1 Our patient's mutation was confirmed by gene sequencing as a structural abnormality in the transthyretin peptide sequence (Tyr69His). This is a recently described base pair substitution at codon 69, which results in heterozygosity for normal tyrosine and variant histidine, which typically presents with the oculoleptomeningeal type of familial amyloid polyneuropathy.2
Under normal circumstances, the transthyretin-type amyloid protein acts as a serum and CSF carrier of thyroxine and retinol-binding protein.3 Transthyretin-type amyloid is secreted into the blood and CSF via the liver and choroid plexus, respectively.1 However, when mutated, transthyretin-type amyloid forms aggregates of misfolded protein, which are deposited in the body, and were presumably responsible for the increased CSF protein seen in our patient.3
Leptomeningeal enhancement along the brain stem and spinal cord was described in transthyretin-type amyloid-related amyloid deposition in 20044 and was thought to be a characteristic finding at that time. The combination of leptomeningeal enhancement and superficial siderosis has been described in previous case reports.5,6 In 1 case, fragile engorged vessels were noted along the spinal cord at the time of biopsy.6
Possible causes of leptomeningeal enhancement that have been proposed include an inflammatory response to the amyloid deposits within the leptomeninges, vascular stasis, or leakage of contrast within abnormal leptomeningeal vessels weakened by amyloid.4–6 Slow leakage of blood into the subarachnoid space from weakened vessels could account for superficial siderosis. The engorgement of the intradural spinal veins in our case may be an inflammatory response to the amyloid deposits or vascular stasis because no arteriovenous shunt surgery was identified on 2 catheter spinal angiograms. To our knowledge, this is the first time that engorged intradural vessels have been described on MR imaging in association with this disease process.
Differential considerations of leptomeningeal enhancement include infectious, inflammatory, granulomatous, and neoplastic meningeal conditions.7 Causes of superficial siderosis include dural abnormalities (eg, meningocele, pseudomeningocele, nerve root avulsion, CSF leak), neoplasms (eg, ependymoma, meningioma, oligodendroglioma), and vascular abnormalities (eg, arteriovenous malformation, aneurysm).8 Oftentimes the cause of siderosis is not found.8 Engorged intradural spinal veins can be present in conditions that result in venous congestion, such as arteriovenous fistula, arteriovenous malformation, or vascular spinal tumor.9 The presence of leptomeningeal enhancement and siderosis in the setting of elevated CSF protein and engorged intradural spinal veins suggests the unifying diagnosis of leptomeningeal transthyretin–related familial amyloidosis.
Presented at the American Society of Neuroradiology 52nd Annual Meeting and Foundation of the ASNR Symposium, May 17–22, 2014, Montreal, Quebec, Canada.
We thank Sonia Watson, PhD, for the assistance of in the preparation of the manuscript.