Faculty Bibliography

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016.

BACKGROUND:Quantitative Sensory Testing (QST) is more often used because of the increasing recognition of small fiber neuropathy. METHODS:We studied QST in a systematic way in an age-stratified cohort of 83 neurological-free Hispanic Latinamerican patients. Predefined standardized stimuli were applied using the method of limits. RESULTS:WDT range from 2.2 to 3.3°C in hands, and from 4.0°C up to 6.6°C in feet. Cold detection threshold range from 2.2 to 3.6°C in hands, and from 2.6°C to 4.5°C in feet. Heat-induced pain (HP) was induced at lower temperatures than previously reported, with a range from 41.8°C to 44.5°C in hands and from 43.2 to 45.7°C in feet. Similar to HP, cold pain was also induced at much higher temperatures, between 21.4-17.3°C in hands and 21.5-16.5°C in feet. Vibratory stimuli ranged from 0.8 to 1.7 μ/sec in hands and from 1.4 to 3.5 μ/sec in feet. CONCLUSION:Temperature and vibration thresholds were similar to those previously reported in other populations except for pain thresholds that were lower in this population than in the Caucasian population.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.

BACKGROUND:Cryptococcal meningitis (CM) is a rare condition in non-HIV patients. The clinical manifestations in patients with systemic lupus erythematosus (SLE) are often confused with immunological activity, resulting in delayed diagnosis. AIMS/OBJECTIVE:We describe the natural history and outcome of eight HIV-negative patients with SLE and confirmed CM. RESULTS:Mean age at the time of infection was 30·2 years (20-42). Mean dose of prednisone was 38·3 ± 13 mg/day and of azathioprine was 95 ± 37 mg/day. The most common clinical manifestation was headache with nausea or vomit (75%), followed by altered sensorium (50%), fever (50%), cranial nerve deficits (37%), or seizures (25%). Mean time between symptoms onset and diagnosis was 19 days (6-56). All patients had low lymphocyte cell counts (504 ± 229 cells/μl) and low CD4+ cell counts (113·2 ± 59·2 cells/μl). Active SLE assessed by a systemic lupus erythematosus disease activity index (SLEDAI) score ≧4 was found in 83% patients at the time of the diagnosis and 87% had renal involvement. The positivity of cryptococcal antigen, India ink stain, and culture in the cerebrospinal fluid (CSF) was 90, 70, and 50%, respectively. Magnetic resonance was abnormal in 90% of the patients. Higher titers of cryptococcal antigen were suggestive of worse outcome and increased hospital stay. After a mean follow-up of 4·9 years, one patient had a relapse of the CM, associated with persistent low CD4+ cell counts. CONCLUSIONS:Cryptococcal meningitis in patients with SLE was associated with severe delay in diagnosis and profound lymphopenia. Follow-up should include CD4+ cell counts, and maintenance treatment with fluconazole should be continued until lymphopenia resolution.

Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms can be non-specific and diagnosis largely relies on amyloid detection in tissue biopsies. Treatment is guided by which tissues/organs are involved, although therapeutic options are limited for patients with late-stage disease. Indeed, enthusiasm for liver transplantation for familial ATTR amyloidosis with polyneuropathy was dampened by poor outcomes among patients with significant neurological deficits or cardiac involvement. Hence, there remains an unmet medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow disease progression in some patients with ATTR amyloidosis with polyneuropathy, and the postulated synergistic effect of doxycycline and tauroursodeoxycholic acid on dissolution of amyloid is under investigation. Another therapeutic approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR concentration can be significantly reduced with ISIS-TTR(Rx), an investigational antisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. The evolving treatment landscape for ATTR amyloidosis brings hope for further improvements in clinical outcomes for patients with this debilitating disease.

OBJECTIVE:To describe 58 subjects with rare TTR mutations, and to compare the different biomarkers between carriers and patients. METHODS:TTR gene sequence test was performed in 15 suspicious subjects and in their direct family. All positive subjects undertook prospective evaluations in a period of 49 months. RESULTS:Of 95 genetic tests performed, 58 (61%) were positive for TTR mutations, Ser50Arg mutation in 38 (65%), Ser52Pro in 15 (26%) and Gly47Ala in 5 (9%). Initial symptoms were neuropathic in 19 (73%), gastrointestinal in 6 (23%) and autonomic in 1 (4%). CONCLUSIONS:The natural history of Ser50Arg, Ser52Pro and Gly47Ala TTR mutations is similar to the Val30Met mutation described in endemic areas. The small fiber assessments were the initial tests to show abnormalities in asymptomatic subjects.

Cocaine-induced leukoencephalopathy is a rare neurological complication. It is most likely related to the substances used to adulterate the cocaine. Levamisole is one of the most common adulterants of cocaine and causes reversible leukoencephalopathy. Patients display severe neurological symptoms that resolve at termination of the exposure. MRI shows diffuse white matter involvement with sparing of the U fibers, without brain stem or cerebellar involvement. We describe the case of a woman with three neurologic episodes and remitting and recurrent brain white matter lesions.

After a decade of steady decline, syphilis has reemerged within the past few years and it is seeping back into the HIV negative population. We describe herein 16 consecutive cases of neurosyphilis and compare its clinical characteristics. Of the 16 patients, 14 (87%) were men. Mean age at onset was 43 years old (range: 23-82). Twelve patients (75%) were HIV positive; stage was B2 in 2 patients, B3 and C2 in one patient each, and C3 in 8 patients. The clinical presentation was meningitis in 6 (40%), stroke in 3 (18%), ocular manifestations in 4 (27%), and psychiatric manifestations in 2 (13%) cases. Five additional patients had ocular involvement after a formal ophthalmologic examination. High venereal disease research laboratory test (VDRL) titers in serum and cerebrospinal fluid (CSF) were found. Patients in C3 stage of HIV had less CSF pleocytosis (<5 cells/mm(3)) than patients in earlier stages (P=0.018). Disease onset was earlier in patients older than 50 years old with HIV (P=0.049). We found that meningitis, ocular manifestations and stroke were the most common clinical findings in early syphilis. Moreover, stroke included the carotid and cerebrobasilar vascular territories. CSF VDRL continues to be a crucial test in all idiopathic cases of meningitis, stroke and uveitis, regardless of the HIV status or CSF pleocytosis. Except for less pleocytosis, there were no important differences between HIV positive and HIV negative patients.