Post-poliomyelitis Muscular Atrophy Research Articles

Adult-onset spinal muscular atrophy with SMN deletion and ultrastructural tubulo-filamentous inclusions identical to inclusion body myositis

Sporadic inclusion body myositis (IBM) is an inflammatory myopathy with the diagnostic criteria on electron microscopy of rimmed vacuoles and 15–18 nm intracytoplasmic/intranuclear tubulofilamentous inclusions. There is a spectrum of neuromuscular diseases with these features and to our knowledge, this is the first case of a genetically proven adult-onset spinal muscular atrophy illustrating inflammation, rimmed vacuoles and tubulofilamentous inclusions. A 53-year-old male presented at 35 years with slowly progressive weakness, unsteady gait and atrophy of thighs and buttocks. His upper limbs and distal legs were unaffected. Sensory examination was normal. There was no dysphagia, ocular disturbance, sphincteric involvement and no family history of a neuromuscular disorder. Serum CK was normal. The EMG and deltoid muscle biopsy showed a neurogenic process. Subsequent quadriceps muscle biopsy histology demonstrated denervation and focal myonecrosis, rimmed vacuoles and sarcoplasmic inclusions. Ultrastructurally, rimmed vacuoles with myelinoid phospholipid whorls and degenerate organelles, intracytoplasmic and intranuclear 16 nm tubular filaments were present. Single strand conformational polymorphism (SSCP) showed homozygous deletions of exons 7 and 8 of the SMN1 gene on chromosome 5q. Our case of genetically proven adult-onset SMA confirms that rimmed vacuoles and 16 nm. IBM-like tubulofilamentous inclusions occur in a primary denervating condition. 1.Dubowitz V, Sewry C, Oldfors A. Muscle Biopsy: A Practical Approach. 5th ed. London: Elsevier, 2021.2.Semino-Mora C, Dalakas MC. Rimmed vacuoles with beta-amyloid and ubiquinated filamentous deposits in the muscles of patients with long-standing denervation (postpoliomyelitis muscular atrophy): similarities with inclusion body myositis. Hum Pathol 1998; 29: 1128–33.

Concomitant CNS pathology in a patient with amyotropic lateral sclerosis following poliomyelitis in childhood

Post-polio syndrome (PPS) develops in approximately 30% of polio survivors several decades after the acute attack of paralytic poliomyelitis. Some of these patients develop post-poliomyelitis muscular atrophy (PPMA) which is characterized by a slowly progressive muscle weakness. Due to its clinicopathological features, investigators have often studied PPS and PPMA in association with amyotrophic lateral sclerosis (ALS), the underlying hypothesis being an increased risk of developing ALS from a prior acute paralytic poliomyelitis. Various studies, however, have indicated that de novo ALS cases in patients with prior acute paralytic poliomyelitis are rare. Herein, we describe a rare case of a 75-year-old woman who at post-mortem examination presented a combination of a PPS with proven histopathological sporadic ALS features. Furthermore, neuropathology of this case also revealed several other histopathological findings reminiscent of a tauopathy, synucleinopathy and amyloid angiopathy and a large pituitary cyst. To our knowledge, this is the first reported case of PPS with clear pathological hallmarks of sporadic ALS, including ubiquitin-, TDP-43, phosphorylated TDP-43- and p62-positive inclusions, with accompanying features compatible with Alzheimer's and Parkinson's disease.

Rimmed vacuoles with β-amyloid and ubiquitinated filamentous deposits in the muscles of patients with long-standing denervation (postpoliomyelitis muscular atrophy): similarities with inclusion body myositis

In the chronically denervated muscles of patients with prior paralytic poliomyelitis, there are secondary myopathic features, including endomysial inflammation and rare vacuolated fibers. To assess the frequency and characteristics of the vacuoles and their similarities with those seen in inclusion body myositis (IBM), we examined 58 muscle biopsy specimens from patients with prior paralytic poliomyelitis for (1) the presence of rimmed vacuoles; (2) acid-phosphatase reactivity; (3) Congo-red-positive amyloid deposits; (4) electron microscopy, searching for tubulofilaments; and (5) immunoelectron microscopy, using antibodies against β-amyloid and ubiquitin. We found vacuolated muscle fibers in 18 of 58 (31%) biopsies, with a mean frequency of 2.06 ± 0.42 fibers per specimen. The vacuoles contained acid phosphatase-positive material in 6 of the 18 (33.30%) specimens and stained positive for Congo red in five (27.80%). By immunoelectron microscopy, the vacuoles contained 5.17 ± 0.13 nm fibrils and 14.9 ± 0.31 nm filaments that immunoreacted with antibodies to β-amyloid and ubiquitin in a pattern identical to the one seen in IBM. We conclude that vacuolated muscle fibers containing filamentous inclusions positive for amyloid and ubiquitin are not unique to IBM and the other vacuolar myopathies but can also occur in a chronic neurogenic condition, such as postpoliomyelitis. The chronicity of the underlying disease, rather than the cause, may lead to vacuolar formation, amyloid deposition, and accumulation of ubiquitinated filaments.

The post-polio syndrome as an evolved clinical entity. Definition and clinical description.

Post-polio syndrome (PPS) refers to the new neuromuscular symptoms that occur at least 15 years after stability in patients with prior acute paralytic polio-myelitis. They include: (1) new muscle weakness and atrophy in the limbs, the bulbar or the respiratory muscles [post-poliomyelitis muscular atrophy (PPMA)] and (2) excessive muscle fatigue and diminished physical endurance. PPS is a clinical diagnosis that requires exclusion of all other medical, neurological, orthopedic or psychiatric diseases that could explain the cause of the new symptoms. Routine electromyography is useful to confirm chronic and ongoing denervation and exclude neuropathies. Muscle biopsy, single fiber electromyography (EMG), macro-EMG, serum antibody titers to polio virus, and spinal fluid studies are very useful research tools but they are rarely needed to establish the clinical diagnosis. PPS is a slowly progressive phenomenon with periods of stability that vary from 3 to 10 years. Current evidence indicates that PPS is the evolution of a subclinically ongoing motor neuron dysfunction that begins after the time of the acute polio. It is clinically manifested as PPS when the well-compensated reinnervating process crosses a critical threshold beyond which the remaining motor neurons cannot maintain the innervation to all the muscle fibers within their motor unit territory.

Pathogenetic mechanisms of post-polio syndrome: morphological, electrophysiological, virological, and immunological correlations.

To understand the mechanism of post-poliomyelitis muscular atrophy (PPMA) and the post-polio syndrome (PPS) in general, we performed the following studies: (1) histopathology in spinal cord sections from patients who died 9 days to 44 years after acute paralytic poliomyelitis; (2) enzyme histochemistry, immunocytochemistry (for lymphocyte subsets, MHC antigens and N-CAM) and polymerase chain reaction (PCR) for poliovirus RNA in the muscle biopsies from symptomatic or asymptomatic muscles of post-polio patients; (3) determination of lymphocyte subsets and circulating IgG or IgM antibodies against GM1 and poliovirus; (4) virological studies in the spinal fluid for oligoclonal bands and search for poliovirus genome with PCR; (5) electrophysiological studies including single fiber EMG, fiber density and macro-EMG; and (6) [31P] exercise MRS spectroscopy on previously affected muscles to search for a metabolic correlate of fatigue. These studies concluded that in PPS a continuing dysfunction is present in the spinal cord motor neurons, resulting in ongoing muscle denervation and reinnervation first evident at the axonal branch points. Symptoms are related to attrition of the oversprouting motor neurons which after a period of time cannot support all their axonal sprouts, resulting in failure of re-reinnervation. In some patients with PPS there is also an ongoing immune activation and presence of defective viral particles in the spinal fluid. However, their role in the pathogenesis of PPS is presently unknown.

Dysphagia in postpolio patients: a videofluorographic follow-up study.

In patients with a history of acute paralytic poliomyelitis (APP), late progressive muscle weakness may arise, known as the progressive postpoliomyelitis muscular atrophy (PPMA). In 43 patients with PPMA, 8 were evaluated for recent or late progressive dysphagia. The mean interval between APP and onset of swallow symptoms was 27.1 years (range 23-45); the mean age of the patients was 45.4 years (range 35-52). Initial videofluorography showed signs of slight-to-moderate oropharyngeal dysfunction in 6 patients (delayed swallow reflex, diminished peristalsis of constrictor pharyngeus muscle, diminished laryngeal elevation, retention of bolus). In 2 patients, no abnormalities were found. Seven patients were reexamined after 12-36 months (mean 18). All reported subjective progression of symptoms. Videofluorography showed minor changes in 1 patient and unaltered findings in 6. No signs of aspiration were found either clinically or by video. We conclude that patients with PPMA complaining of late dysphagia do not show a significant loss in oropharyngeal function on 1-3 years follow-up.

Macro EMG follow-up study in post-poliomyelitis patients.

We investigated the muscle strength and motor unit (MU) territory of five patients with postpolio syndrome (PPS), six stable patients with prior poliomyelitis, and five healthy volunteers. The MU territory was assessed by measuring amplitudes of motor unit potentials (MUPs) recorded by the macro EMG technique. The investigations were repeated after 11-20 months (mean 15.6). The macro MUP amplitudes in both patient groups were markedly increased (P = 0.02). However, no statistical difference was found between the two groups in the initial amplitude values. Macro MUP amplitudes obtained on repeated examinations did not differ significantly from the initial macro MUP amplitudes in any of the three groups. In three individual PPS patients, a decline in muscle strength on the follow-up study was documented, providing the diagnosis of post-poliomyelitis muscular atrophy (PPMA). The three PPMA patients had the highest initial macro MUPs. Two of them showed a decrease in macro MUP amplitudes on follow-up. These findings suggest that a later breakdown of oversized MUs may play a role in the pathogenesis of PPMA.

Clinical and electromyographic studies of postpoliomyelitis muscular atrophy

Eleven patients with progressive weakness following polio (postpoliomyelitis muscular atrophy syndrome) were compared electromyographically with nine patients who had stable strength following polio. Abnormalities included (1) abnormal motor unit characteristics in many muscles indicating widespread loss of motor neurons and reinnervation in muscles, including many not clinically affected by the polio; (2) prevalent spontaneous denervation potentials; and (3) abnormal single-fiber electromyographic jitter. These electromyographic abnormalities were similar in progressive and stable postpoliomyelitis patients even when muscles were separated by strength, stability, age and duration of the postpoliomyelitis state. Postpoliomyelitis muscular atrophy appears to be the clinically apparent end of the spectrum of abnormalities existing in all postpoliomyelitis patients.

Inclusion body myositis in post-poliomyelitis muscular atrophy

A 38-year-old male developed a new muscle weakness in his left thigh 35 years after having acute paralytic poliomyelitis with residual right distal leg weakness and atrophy. EMG studies showed widespread denervation in proximal and distal muscles regardless the clinical involvement. Muscle biopsy from an affected muscle showed the findings of inclusion-body myositis consisting of perivascular and interstitial mononuclear infiltration, sarcoplasmic granular inclusions with membranous whorls and typical filamentous inclusions in several myonuclei. This raises the possibility of inclusion body myositis in other cases of progressive post-poliomyelitis muscular atrophy, especially those with perivascular infiltration of mononuclear cells in the muscle biopsy.

Functional recovery. A major risk factor for the development of postpoliomyelitis muscular atrophy.

A retrospective study was undertaken to identify potential risk factors for the development of progressive postpoliomyelitis muscular atrophy (PPMA). Patients with PPMA (n = 57) were compared with patients with a history of poliomyelitis but without a history of progressive weakness (n = 49). Patients who later developed PPMA had histories of more widespread acute paralysis, but relatively greater functional recovery. They were less disabled, and reported higher recent activity levels. Seventy-nine percent of the total variance between the PPMA and control groups could be accounted for by recovery alone (ie, severity minus disability). Functional recovery is generally attributed to reinnervation of sarcomeres by collateral sprouting from surviving lower motor neurons. Since degree of recovery predicts the risk of developing PPMA, our findings suggest that enlarged motor units may carry an increased susceptibility for dysfunction and/or degeneration.

The Late Sequelae of Poliomyelitis

Progressive functional deterioration following poliomyelitis has been reported after a prolonged period of stability. We present follow up data on 209 patients; the period from the original illness to December 1985 or death was between two and 73 years (mean 33.9). One hundred and sixty-three (78 per cent) patients developed late functional deterioration. This was due to purely respiratory factors in 99 cases, new neurological signs in 20 cases, and orthopaedic problems in 17 cases; 31 patients deteriorated due to a combination of factors. The commonest cause of respiratory deterioration was the development of nocturnal alveolar hypoventilation, sometimes associated with late progressive scoliosis. Eighty-six patients needed respiratory support beginning between one year and 66 years (mean 28.5) after the acute illness. New neurological signs had a clearly defined cause in each of 20 patients. No cases of motor neurone disease or post-poliomyelitis muscular atrophy (PPMA) were identified. This series shows that late sequelae following poliomyelitis are common. There were no patients with functional deterioration after poliomyelitis in whom a clear underlying cause could not be shown. The major causes of deterioration may be treatable or avoidable, and in particular, those who develop chest infections or new respiratory symptoms should be treated with caution as respiratory failure may rapidly supervene.

Review article : The late effects of poliomyelitis: aetiology and rehabilitation

Decades after their acute infection, many polio survivors are suffering renewed muscle weakness, increasing respiratory difficulties, musculoskeletal pain, fatigue and cold intolerance which lead to a 'second disability'. Some symptoms are due to chronic mechanical strain caused by using joints rendered unstable after the acute infection. The cause of others, such as postpoliomyelitis muscular atrophy, is . unknown although overuse, ageing, disuse atrophy and metabolic fatigue of axon sprouts in the abnormally large motor units may play a role. The aim of rehabilitation is to halt the progress of the condition and reduce its physical and psychological impact. Reduction in strenuous activity is important. The use of orthoses or a wheelchair may help to reduce pain and the energy cost of mobility. Respiratory aids such as the cuirasse can improve health. Counselling and peer group support can help the patient to accept his physical limitations.

New neuromuscular symptoms in patients with old poliomyelitis: a three-year follow-up study.

Fourteen survivors of paralytic poliomyelitis experienced new symptoms after years of stability. Seven patients had lost functional capacity, with joint pain, instability and recurrent falls, but were again stable and remained essentially unchanged during a 3-year follow-up period. Seven others had late postpoliomyelitis muscular atrophy (PPMA) with new weakness, wasting, fasciculations and myalgia in muscles originally spared or seemingly recovered. Muscle biopsy from newly affected muscles showed new and chronic denervation with interstitial inflammation in 3 patients. Antibody titers to poliomyelitis virus were not elevated in the CSF, but oligoclonal IgG bands were found in 3 PPMA patients. During the 3-year follow-up period, PPMA patients showed signs of slow progression which continued to be focal. It is concluded that the new symptoms in postpolio patients may be musculoskeletal and relatively stable, or due to a slowly progressive, focal, and apparent benign new motor neuron deterioration.