A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline over a 19-month period. He presented initially in March 2011 with weight loss of 20 kg over 3 months. Two months later, he developed progressive confusion, fatigue, erectile difficulties, urinary urgency and incontinence. In March 2012, he suffered from recurrent episodes of slurred speech and right-sided weakness, lasting 30 min. At his local hospital, a non-contrast MRI head was normal, but an echocardiogram identified a restrictive cardiomyopathy and he was started on aspirin. The episodes were initially every 2 weeks but increased in frequency over time. In June 2012, he developed new left-sided hearing difficulties. By October 2012, he had developed painless paraesthesia in both feet.
There was no relevant past medical history. His father had suffered from weight loss, erectile dysfunction and renal problems, and died of a myocardial infarction in his 60s. His mother died in her 50s of unknown cause. Of his four siblings, the oldest brother died at age 14 but no clear cause was established. His sister had developed deafness in her 40s.
Cardiovascular, respiratory and abdominal examination was unremarkable. Screening cognitive testing demonstrated anterograde memory difficulties, and impairment of attention and concentration; the MMSE score was 21/30. He had horizontal gaze-evoked nystagmus and a brisk jaw jerk, but cranial nerve examination was otherwise normal. Neuro-ophthalmological assessment was normal. Examination of the limbs revealed increased tone and brisk reflexes in the upper and lower limbs and mild bilateral heel-shin ataxia.
The following blood tests were normal or negative: Full blood count, urea and electrolytes, liver function tests, thyroid function, cardiac enzymes, B12, folate, serum ACE, HIV, HTLV-1, and treponemal serology, ANA, ANCA, anti-neuronal antibodies, serum-free light chain assay, electrophoresis and immunofixation. Urine testing confirmed a normal creatinine clearance and no proteinuria. On the basis of the autonomic symptoms and restrictive cardiomyopathy, sequencing of the TTR gene was performed, revealing that he was heterozygous for the mutation leucine 12 proline.
Magnetic resonance imaging (MRI) of the brain and spine showed extensive leptomeningeal enhancement over the surface of the brain and spinal cord (Fig. 1). No signal change was demonstrated within the underlying parenchyma. Susceptibility-weighted sequences revealed no parenchymal microhaemorrhages, or evidence of subarachnoid blood products. Magnetic resonance angiography of the intra- and extra-cranial arteries was normal. There was also evidence of mild, diffuse thickening of the intrathecal nerve roots, and nerves of the brachial and lumbosacral plexus (Fig. 2).  
Cerebrospinal fluid (CSF) analysis showed seven white cells (four lymphocytes and three polymorphs), CSF protein was elevated at 6.4 g/dl, with a normal glucose ratio (3.6 mmol/l CSF and 5.9 mmol/l serum), oligoclonal bands were not detected. Whilst the CSF Ab1-42 was depressed (371 pg/ml, reference range 627-1,322) possibly reflecting sequestration within CNS amyloid plaques as is seen in Alzheimer's disease (AD), unlike in AD the CSF tau level was also low (107 pg/ml, reference range 146-595) mitigating against an ongoing neurodegenerative process. Two further CSF examinations showed a mild pleocytosis and persistently raised CSF protein. No organisms were cultured (including mycobacterium tuberculosis) and no cellular atypia was seen.
Nerve conduction studies demonstrated a mild large fibre peripheral neuropathy in the lower limbs and a severe small fibre neuropathy affecting both the upper and lower limbs. Autonomic function testing showed a low resting supine blood pressure (BP) of 101/65 mmHg and orthostatic hypotension on standing at 3 min with BP dropping to 77/50 mmHg. A 48-h period of inpatient video telemetry showed mild global cortical dysfunction but no focal features or epileptiform abnormalities.
Neuro-otology investigations confirmed a mixed left-sided peripheral and central vestibular disorder with sparing of the auditory pathway. Neuropsychometry testing showed profoundly impaired processing speed with widespread cognitive impairment reflecting severe subcortical dysfunction.
A brain biopsy was performed to confirm amyloid deposition and exclude any other pathology. The histology confirmed widespread amyloid angiopathy involving dura mater, leptomeninges and neocortical blood vessels as well as occasional vessels in the white matter. There was no evidence of underlying malignancy or vasculitis. (see Fig. 3). 
Serum amyloid P component scintigraphy demonstrated the modest amyloid deposits in the spleen and kidneys.
ECG revealed sinus rhythm with small complexes in the inferior leads. Echocardiogram demonstrated an ejection fraction of 51 %, mild to moderate diastolic dysfunction with elevated filling pressures. Cardiac MRI showed moderate left ventricular (LV) wall thickening and moderate LV systolic dysfunction, along with diffuse biventricular late gadolinium enhancement typical of cardiac amyloidosis. TC-labelled DPD scintigraphy showed grade III localization in the heart, characteristic of cardiac TTR amyloidosis.
Arterial blood gas sampling demonstrated central hypoventilation causing respiratory failure.
During his inpatient stay he continued to deteriorate, remaining very drowsy with fluctuating agitation and confusion. Liver transplantation was considered but excluded due to the lack of evidence for benefiting TTR amyloidosis patients with CNS disease, along with the presence of cardiac amyloidosis and the rapid deterioration of the patient's cognitive function. He was subsequently repatriated to his local hospital. At the time of writing, he has spent 330 days in hospital. There has been a gradual decline in his overall condition. He has developed an atonic bladder, with recurrent urosepsis and now has an indwelling catheter.