Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
In April 2009, a 59-year-old Afro-Caribbean man gave a 6-month history of progressive unsteadiness and falls. He reported heavy legs, tiredness on walking and painless paraesthesia below the knees. There were cramps in his hands, with weakness when attempting to open jars.
He had a previous diagnosis of achalasia, for which he had sought medical attention 1 year before developing neurological symptoms. He had reported dysphagia to solids and liquids, with 10 kg weight loss. Barium swallow showed barium hold up in the distal oesophagus, tapering to a beak-like appearance. Oesophageal manometry showed elevated lower oesophageal sphincter pressure, with failure to relax on swallowing, consistent with achalasia. This was managed with two cycles of botulinum toxin injections to the lower oesophageal sphincter and oesophageal dilatation, initially with good results. He took ferrous sulfate for an unspecified anaemia. There was no toxin exposure or alcohol overuse, but he smoked marijuana occasionally. There was no relevant family history.
On examination, there was wasting below the knees and in the small hand muscles, with distal symmetrical weakness. He had only a flicker of movement in the hallux and small muscles of the hands and mild weakness of movements around the ankle and finger extensors. He was areflexic. Sensory examination showed ‘stocking-and-glove’ sensory loss to light touch; vibration sense was present at the ankles, but proprioception present only for large movements of the hallux. Pinprick sensation was normal. General examination was normal.
Nerve conduction studies showed a severe sensorimotor polyneuropathy, which was predominantly axonal, though with subtle demyelinating features (prolonged or absent F waves, table 1). Needle electromyography showed pronounced subacute denervation in the first dorsal interosseous and tibialis anterior muscles. There was borderline anaemia (haemoglobin 120 g/L) with macrocytosis (MCV 103 fL) and an elevated erythrocyte sedimentation rate (75 mm/first hour). Normal or negative investigations included urea and electrolytes, liver function tests, random plasma glucose, vitamin B12, folate, creatine kinase, serum protein electrophoresis, urine Bence Jones protein and immunofixation, HIV, HTLV, hepatitis B, C, syphilis and Lyme serology; rheumatoid factor, ANA, ANCA, C3/C4, antiganglioside, anti-MAG, anti-VEGF and antineuronal antibodies. CSF was acellular with normal protein concentration. We excluded occult malignancy on CT chest–abdomen–pelvis and PET scanning. MR scan of the neuroaxis showed only mild cervical spondylosis. Sural nerve biopsy showed severe axonal loss, but with mild demyelination and significant T-lymphocyte infiltration, in keeping with an inflammatory neuropathy, with no vasculitis or amyloid.
We treated him with intravenous immunoglobulin, then prednisolone for a presumptive diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Despite a possible initial response, he became progressively weaker over the next 6 months; repeat nerve conduction studies confirmed disease progression. We added mycophenolate mofetil, and while on this, his dysphagia recurred and he developed diarrhoea. He continued to progress over the subsequent year and was treated with rituximan then cyclophosphamide for presumed severe progressive refractory CIDP.
His weight loss, diarrhoea and weakness progressed to the extent that 3 years after presentation he could not walk unaided. Upper gastrointestinal endoscopy and colonoscopy were macroscopically normal, with gastric, duodenal and colonic biopsy specimens reported as unremarkable. He developed a pulmonary embolus requiring anticoagulation and was admitted to hospital with aspiration pneumonia, related to recurrence of achalasia.
His failure to respond to immunomodulatory treatment and his pronounced gastrointestinal features prompted re-evaluation of the diagnosis. The National Amyloidosis Centre Gastrointestinal re-examined his nerve biopsy specimens and found amyloid in gastric and colonic biopsies. The amorphous material stained with Congo red, with apple-green birefringence under cross-polarised light and positive staining to transthyretin antibodies (figure 1). The nerve biopsy showed no amyloid. Genetic analysis showed a heterozygous mutation (Val30Met) in the transthyretin gene, confirming familial amyloid polyneuropathy. Echocardiography and DPD scintigraphy confirmed cardiac involvement. We referred him for genetic counselling and listed him for enrolment in future clinical trials of new medical therapies.
Transthyretin-related familial amyloid polyneuropathy is an autosomal-dominant subtype of amyloidosis, characterised by deposits composed of mutant transthyretin. Neurological involvement usually presents as length-dependent painful neuropathy with prominent autonomic impairment, progressing to motor weakness, with symptom onset typically after 40–50 years of age.
Familial amyloid polyneuropathy may be confused with CIDP,1 especially in non-familial cases such as this. Our patient had no pain nor autonomic features at presentation, and there were subtle demyelinating changes on neurophysiology and T call infiltration on the nerve biopsy, with no amyloid in his nerve, even on review. These features, with a rapid clinical course, made CIDP a possible diagnosis, even without a raised CSF protein.
The Val30Met substitution is the most common mutation worldwide and is endemic in Portugal, Sweden and Japan,2 rare in the Afro-Caribbean population. His detailed family history was negative, consistent with the variable penetrance of transthyretin gene mutations.
In endemic areas, clinicians should consider the diagnosis in the setting of a sensorimotor or autonomic neuropathy with an appropriate family history. Without a family history, the diagnosis should be considered in patients with progressive axonal neuropathy, particularly with cardiac or autonomic dysfunction. Dysphagia may occur in amyloidosis; occasional patients with transthyretin-related familial amyloid polyneuropathy have sudden onset dysphagia mimicking achalasia.3
Although there are usually amyloid deposits in affected tissues on microscopy, it is important to recognise that negative biopsy findings do not rule out the diagnosis, though inflammatory features in nerves, as occurred here, are unusual. In this setting, genetic testing can help, even without a family history.2
Late diagnosis of familial amyloid polyneuropathy, which occurs especially in non-familial cases, has adverse consequences. It will delay appropriate, disease-specific treatment and genetic counselling. Our patient was also exposed to the risks of immunosuppressive therapy for the putative diagnosis of CIDP. Liver transplantation is currently the only established treatment for familial amyloid polyneuropathy associated with the Val30Met variant. Transplantation typically stabilises but may not reverse the neuropathy and can be precluded by cardiac involvement, as was the case here. This is due, in part, to paradoxical acceleration of cardiac amyloidosis post-transplantation. Several novel medical therapies are currently under trial. One approach is to attempt kinetic stabilisation of the transthyretin tetramer using medications such as tafamidis.4 A recently described novel therapeutic approach using RNA interference (RNAi) can safely and effectively reduce transthyretin levels.5
This was an unusual case of transthyretin amyloidosis presenting with achalasia and what appeared to be inflammatory demyelinating neuropathy. Transthyretin-related familial amyloid polyneuropathy can mimic CIDP, particularly early in the disease, and amyloid deposits may be patchy and even absent on nerve biopsies. In refractory CIDP, clinicians should consider testing for transthyretin gene mutations, even without a family history. Patients need an early diagnosis to obtain maximum benefit from liver transplantation, currently the only established treatment, though new medical therapies using novel therapeutic approaches offer hope for the future.
Contributors All authors had access to the data and a role in writing the manuscript. MG and CMG wrote the draft manuscript. JAG provided the histology slides and wrote the legend for Figure 1. JH, JND and CJW contributed to drafting of the manuscript.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by John Winer from Birmingham, UK.