Teresinha Evangelista

Motor neuron disease presenting with respiratory failure

Respiratory failure accounts for the majority of deaths in amyotrophic lateral sclerosis (ALS) but only rarely is ALS diagnosed on the basis of respiratory insufficiency. We report four ALS patients presenting with acute respiratory failure. In three patients we have performed EMG needle examination of both hemidiaphragms which showed severe denervation. We reviewed 25 patients previously described presenting with respiratory failure. Almost all patients showed upper limbs weakness and diaphragm involvement; few patients had bulbar dysfunction. The prognosis of these patients is not always in permanent ventilator dependence. Rapidly progressive ventilatory failure may be a striking initial sign of ALS; the main reason is a weakened diaphragm. There are possibilities of significant improvement after a period of rest with ventilatory assistance. In the initial phase of the disease, bulbar dysfunction is not the more common reason of acute respiratory failure.

A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis

Abstract Our objective is to describe the results of a phase II/III, 12-months, double-blinded, single-centre, randomized, parallel (1:1), clinical trial performed to evaluate the efficacy and safety of memantine in ALS. Patients with probable or definite ALS of less than 36 months disease duration and progression over a one-month lead-in period were randomly assigned to placebo or memantine at 20 mg/day. The primary endpoint was 12-months ALSFRS decline. Forced vital capacity, manual muscle testing, visual analogue scale, quality of life, motor unit number estimation and neurophysiological index were the secondary endpoints. The number of patients included was based on the assumption of a 50% change in the ALSFRS decline. Safety and adverse events were evaluated. Sixty-three patients were included in the trial. Memantine did not show more adverse events or laboratory changes than placebo. Primary and secondary outcomes were not different between groups by intention-to-treat and per-protocol analysis. The most sensitive measurements were neurophysiological, which declined linearly over time. In conclusion, the results of this study show that memantine is well tolerated and safe in ALS patients. We did not observe any evidence of efficacy for memantine but we cannot exclude a positive outcome on survival.

Botulinum toxin type-B improves sialorrhea and quality of life in bulbaronset amyotrophic lateral sclerosis

BackgroundSialorrhea is a disabling problem in bulbaronset amyotrophic lateral sclerosis (ALS). Botulinum toxin (BTX) type A and B have been proposed as alternatives to traditional treatments.ObjectivesTo evaluate the efficacy and safety of BTX type B in the treatment of sialorrhea in patients with bulbar-onset ALS.MethodsOpen-label prospective study of BTX type B injections in parotids (1000 U) and submandibular (250 U) glands using anatomic landmarks. Primary outcome was rate of responders (improvement > 50% on visual analogue scales (VAS) of severity and disability of sialorrhea) 1 month post-treatment. Other outcomes included subjective (drooling and quality of daily living questionnaires) and objective (cotton roll weights and number of paper handkerchiefs used) evaluations. Safety evaluations included questionnaires regarding brain stem symptoms.ResultsSixteen ALS patients were included. At 1 month the rate of responders was 75% with a mean reduction of 70% in severity and disabling VASs. Fifteen patients (94 %) reported some benefit with drooling reduction. In objective measurements there was a reduction over 60 % in saliva production and in the number of handkerchiefs used. Onset of effect occurred within 3 days. Most patients reported better quality of living. The most frequent side-effects were viscous saliva, local pain, chewing weakness and respiratory infection. There were no changes in blood pressure or cardiac rate. At 3 months, there was still a positive effect in all outcomes. All patients except one manifested their willingness to repeat treatment.ConclusionsAnatomic guided BTX type B injections seem effective and safe to treat sialorrhea in bulbar-onset ALS.

Liver and muscle in morbid obesity: the interplay of fatty liver and insulin resistance.

Introduction Nonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. The muscle is a central player in the adaptation to energy overload, and there is an association between fatty-muscle and -liver. We aimed to correlate muscle morphology, mitochondrial function and insulin signaling with NAFLD severity in morbid obese patients. Methods Liver and deltoid muscle biopsies were collected during bariatric surgery in NAFLD patients. NAFLD Activity Score and Younossis classification for nonalcoholic steatohepatitis (NASH) were applied to liver histology. Muscle evaluation included morphology studies, respiratory chain complex I to IV enzyme assays, and analysis of the insulin signaling cascade. A healthy lean control group was included for muscle morphology and mitochondrial function analyses. Results Fifty one NAFLD patients were included of whom 43% had NASH. Intramyocellular lipids (IMCL) were associated with the presence of NASH (OR 12.5, p<0.001), progressive hepatic inflammation (p = 0.029) and fibrosis severity (p = 0.010). There was a trend to an association between IMCL and decreased Akt phosphorylation (p = 0.059), despite no association with insulin resistance. In turn, hepatic steatosis (p = 0.015) and inflammation (p = 0.013) were associated with decreased Akt phosphoryation. Citrate synthase activity was lower in obese patients (p = 0.047) whereas complex I (p = 0.040) and III (p = 0.036) activities were higher, compared with controls. Finally, in obese patients, complex I activity increased with progressive steatosis (p = 0.049) and with a trend with fibrosis severity (p = 0.056). Conclusions In morbid obese patients, presence of IMCL associates with NASH and advanced fibrosis. Muscle mitochondrial dysfunction does not appear to be a major driving force contributing to muscle fat accumulation, insulin resistance or liver disease. Importantly, insulin resistance in muscle might occur at a late point in the insulin signaling cascade and be associated with IMCL and NAFLD severity.

DOMINANT AND RECESSIVE RYR1 MUTATIONS IN ADULTS WITH CORE LESIONS AND MILD MUSCLE SYMPTOMS

Ryanodine receptor gene (RYR1) mutations have been associated with central core disease (CCD), multiminicore/minicore/multicore disease (MmD), and susceptibility to malignant hyperthermia (MH).

Acquired amyloid neuropathy in a Portuguese patient after domino liver transplantation.

Familial amyloid polyneuropathy (FAP) is a progressive neuropathy with autonomic dysfunction. Domino liver transplantation (DLT), in which the liver of an FAP patient is transplanted into another patient, is routinely applied to compensate for the shortage of available organs. We report a patient who developed a clinical picture of FAP 9 years after a DLT from an FAP donor. Electrophysiological, neuropathological, and autonomic tests were administered. The patient presented with typical clinical features of FAP. Electrophysiological investigation confirmed a moderate sensorimotor axonal and autonomic neuropathy. Sural nerve biopsy confirmed the presence of amyloid deposits in the endoneurium. Skin biopsy at the ankle showed reduced intraepidermal nerve fiber density. Our report shows that FAP can develop in a recipient of an FAP liver. This suggests that careful longitudinal study is required to evaluate the risk of FAP polyneuropathy in patients who undergo domino liver transplantation. Muscle Nerve, 2010

Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy

A middle age Portuguese woman was investigated for renal amyloidosis. She presented with progressive renal failure, proteinuria, hypertension, and sensory symptoms in the feet. Clinical and neurophysiological evaluation disclosed sensory-autonomic neuropathy. Cardiovascular tests and 123-MIBG investigation showed parasympathetic dysfunction and decrease of myocardial innervation, in accordance with small fiber neuropathy, as usually observed in amyloidosis. Immunohistochemical studies revealed AFib amyloidosis and genetic studies the amino acid exchange Glu526Val of the fibrinogen Aα-chain mutation, which was also present in one of her sons. The mutant gene in this patient was associated with the same haplotype as all other reported cases of Glu526Val mutations. This is the first reported AFibamyloidosis in Portugal, and the first case of AFib in which sensory and autonomic nerve fiber dysfunction is described, indicating that small nerve fiber lesion can occur in the fibrinogen Aα chain mutation. This can be important for prognosis, in particular when liver transplantation is considered for treatment.

Atypical phenotype in two patients with LAMA2 mutations

Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the α2-chain of laminin. We report two patients with partial laminin-α2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation).

Bilateral phrenic nerve neuropathy in a diabetic patient; TO THE EDITOR

Bilateral phrenic nerve neuropathy leading to diaphragmatic palsy as a complication of diabetes was reported only once (White et al., 1992). We report a second case. Our case shows that the ventilatory support with BiPAP can be a very useful treatment in patients with phrenic nerve lesion and respiratory impairment. A 70-year-old man presented with a 9 month history of dyspnoea on exertion and orthopnoea, without other pulmonary or cardiac symptoms. The patient was treated for heart failure in spite of increasing orthopnoea. He had a past medical history of Type 2 (non-insulin-dependent) diabetes mellitus for 10 years. He denied eye, renal, heart or brain complications. He had no previous respiratory symptoms. He had never experienced any episode of severe shoulder pain. He was not taking other medication apart from anti-diabetic drugs and he was not a smoker. The family history was unremarkable. On examination he had limited respiratory excursion with the excessive use of accessory muscles. He experienced orthopnoea and paradoxical abdomino-thoracic motion was present when lying supine. Neurological examination disclosed no atrophy, fasciculations or weakness. No sensory impairment was detected. Blood analysis was normal except for hyperglycaemia (150 mg/dl, normal < 110). A chest radiograph showed elevated hernidiaphragms. A thoracic CT scan performed twice ruled-out pulmonary disease or mediastina] mmour. The forced vital capacity was decreased (1.8 1, 60% of predicted normal value) and it was impossible to perform this test with the patient lying flat because he developed rapid severe orthopnoea. Blood gases showed resting mild hypoxaemia (73 mmHg) and hypercapnia (43 m H g ) , with normal pH (7.35). Motor