Post-polio syndrome: Pathophysiological hypotheses, diagnosis criteria, medication therapeutics




Abstract


Post-polio syndrome (PPS) refers to a clinical disorder affecting polio survivors with sequelae years after the initial polio attack. These patients report new musculoskeletal symptoms, loss of muscular strength or endurance. PPS patients are tired, in pain and experience new and unusual muscular deficits, on healthy muscles as well as deficient muscles initially affected by the Poliovirus . Once a clinical diagnosis is established, the therapeutic options can be discussed. Some pathophysiological mechanisms have been validated by research studies on PPS (inflammatory process in cerebrospinal fluid [CSF] and cytokines of the immune system). Several studies have been conducted to validate medications (pyridostigmine, immunoglobulin, coenzyme Q10) or physical exercises protocols. This article focuses on the relevance and efficacy that can be expected from these therapeutics. Very few studies reported some improvements. Medications combined to individual and supervised exercise training programs are promising therapeutic strategies for PPS patients care management.


Résumé


Le syndrome post-poliomyélitique (SPP) est un diagnostic clinique. Il touche les personnes avec des séquelles de poliomyélite qui se plaignent de nouveaux troubles musculosquelettiques, d’une perte de force ou d’endurance musculaire. Un patient avec un SPP est fatigué, douloureux et perçoit de nouvelles déficiences musculaires inhabituelles, que ce soit sur des muscles sains ou déficients à la suite de l’infection par le Poliovirus . Une fois le diagnostic clinique établi, les alternatives thérapeutiques peuvent être discutées. Certains mécanismes physiopathologiques ont été validés par des travaux de recherche (dysrégulation inflammatoire dans le liquide céphalorachidien et cytokines). Un certain nombre de travaux ont été menés pour valider des procédures thérapeutiques médicamenteuses ou des protocoles d’exercices physiques. Cet article fait le point sur l’intérêt et l’efficacité attendue de ces thérapeutiques. Peu d’études thérapeutiques ont conclu à des effets positifs. Les traitements médicamenteux combinés à des exercices physiques individualisés et supervisés apparaissent comme des stratégies thérapeutiques prometteuses pour la prise en charge de personnes atteintes d’un SPP.


1


English version


1.1


Introduction


Acute anterior poliomyelitis or Heine-Medin disease corresponds to an infectious attack of the motor neurons by the Poliovirus (single-stranded RNA Enterovirus belonging to the Picornavirus group).


Before vaccines became available, this virus affected more than 600 000 children per year. The last great epidemics (pandemics) occurred in the 1950s. Poliomyelitis is an infectious disease of the neurological system and is the one causing the most motor disabilities in the world: 55,000 patients with polio sequelae in France, 700,000 in Europe, 20 millions in the world . Years after these great epidemics and at least 15 years after the initial polio attack, new symptoms are reported in polio survivors. Several different studies and sharing the longitudinal follow-up of their cohorts led to the discovery of a nosological entity: post-polio syndrome (PPS) . Diagnostic criteria were established. No additional exam is capable nowadays of identifying with certainty this syndrome. According to the studies, PPS prevalence is estimated between 20 and 60% , which excludes the psychological consequences related to the past history of this viral infection . Once the diagnosis is established, a therapeutic needs to be defined and adapted to PPS. This work is a review of the literature on useful therapeutic procedures and their expected efficacy to treat patients with PPS.


1.2


Criteria for the diagnosis of post-polio syndrome


Several authors suggested criteria for PPS diagnosis. We mainly find the clinical trio including fatigue, pain and deterioration of the motor deficits. These non-specific symptoms must be detailed and we will focus here on Halstead et al. criteria validated by a college of international experts:



  • •

    a prior episode of paralytic polio confirmed by history, physical exam, and typical findings on EMG;


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    a period of partial or complete neurological recovery (that could have lasted several years) followed by;


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    an extended interval of neurological and functional stability that lasted over 15 years;


  • •

    quick or progressive loss of endurance and/or muscular strength with or without muscular atrophy in previously unaffected and healthy muscles, associated to a general muscle and joint fatigue and cold intolerance;


  • •

    these symptoms are specific by their unusual and lengthy characteristics (progressing for more than 1 year). Other more rare symptoms can be noted (sleep disorders, respiratory disorders, dysphagia, dysarthria, fasciculations, joint deformities).



PPS is an exclusion diagnosis ( Table 1 ): it is essential to exclude all other potential medical or surgical causes that could be responsible for these non-specific new symptoms before validating the PPS diagnosis. The existence of this nosological entity has been the object of discussions and controversies: natural or pathological evolution? We will refer here to the study of Munin et al. who followed polio patients over a 3-year period. Every 6 months, they evaluated the muscular strength in the quadriceps in isometric and isokinetic settings without finding any significant strength decrease (controlled study). Thus, the natural history of poliomyelitis does not necessarily progress towards an aggravation or extension of the motor deficits. Then, how do we explain the pathophysiology of PPS?



Table 1

Non-exhaustive listing of differential diagnoses for PPS.





































Hypothyroidism
Other endocrinal disorders
Respiratory disorders
Sleep apnea syndrome
Cardiac insufficiency
Rheumatoid polyarthritis
Other joint affections
Hematological affections (anemia)
Neoplasia
Adult spinal muscular atrophy
Amyotrophic lateral sclerosis
Cauda equina syndrome
Cervical spondylotic arthritis
Lumbar spinal canal stenosis
Multiple sclerosis
Myasthenia
Radiculopathy


1.3


Pathophysiology of PPS


PPS is related to the death or structural and functional dysfunction of the enlarged surviving motor units . Humans are the only hosts for the Poliovirus . This virus specifically targets the motoneurons of the anterior horn cells of the spinal cord and the brainstem. Its multiplication is responsible for an apoptosis of the affected motoneuron. Secondly, the adjacent motoneurons re-innervate orphaned muscle fibers that have been denervated by acute polio infection creating giant motor units. After the initial infection, a partial or complete recovery occurs. Understanding the pathophysiological history of this infectious disease is essential to better understand the onset of new symptoms and deficits in apparently healthy areas due to a secondary dysfunction of these enlarged motor units and their axonal terminal endings. These dysfunction mechanisms are badly understood and several hypotheses are suggested:



  • •

    persistence of genetic viral materials able to stimulate and deregulate the inflammatory and immune system response, locally, in the central or peripheral nervous system (the old hypothesis of an inactive and persistent virus is totally excluded);


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    imbalance between degenerative and regenerative physiological processes of the enlarged motor units (probably related to an alteration of the regulation mechanisms);


  • •

    structural and functional abnormalities of the muscle fibers and/or abnormal sensorymotor integration (primary or secondary).



Neuromuscular compensation processes during denervation.


Poliomyelitis is a model of chronic denervation: it is important to understand the compensation mechanisms when studying the activation of partially denervated muscles during physical rehabilitation. The structure of muscle fibers inside partially denervated muscles changes according to the activation pattern: the fibers of the Tibialis anterior go from type II (fast twitch, glycolytic) fibers to type I (slow twitch, oxidative) fibers . Altered phenotypic expression of the isoforms such as myosin light chains and myosin heavy chains (respectively MLC and MHC) associated with changes in contractile properties (fibers’ shortening speed) in type 1 fibers have been described . These structural changes explain in part the difficulties in adapting to the mechanical constraints of denervated muscles.


Denervation also induces metabolic changes: some authors observed a decrease in energy production capacity of type 1 fibers on muscles of polio survivors, causing a greater fatigability compared to control fibers .


A quick partial muscle denervation is followed by a certain number of motor neurons, which develop terminal axon sprouts to re-innervate muscle fibers left orphaned by the death of their original motor neurons. The onset of enlarged motor unit is clearly identifiable on EMG recordings and validates this phenomenon .


However, we can observe instability on the long-term course of this re-innervation process, with a size decrease of the enlarged motor units, which progressively loose their terminal axon sprouts. This process seems to be aggravated by intense muscle overuse . A prospective study on the macro motor unit potential (MUP) amplitude on two muscles affected by polio sequelae, Biceps Brachii and Tibialis anterior, showed increase in the macro MUP amplitude of the Tibialis anterior muscle, indicating an ongoing denervation-reinnervation process, whereas it was not modified in the Biceps Brachii. This most likely indicates a more pronounced ongoing denervation-reinnervation process over time in the Tibialis anterior. The authors suggest that a muscle with a more intense and regular activity is subject to a more intense denervation-reinnervation process . We can suppose that excessive muscle use might be harmful for PPS and generate a greater fatigue .


To sum up, there are some arguments in favor of the peripheral mechanisms being the source of the loss of muscular strength and neuromuscular fatigue in case of chronic denervation. However, fatigue can have a central origin as suggested by Lupu et al. . These authors studied the motor responses to a transcranial magnetic stimulation (motor evoked potentials) in a group of polio survivors and in a control group. After a series of standardized efforts, the motor response was weaker in the polio survivors group suggesting an alteration of the motor cortex capacity to command a locomotor action. This validates the fact that there is a central component to this fatigue.


1.4


Efficacy of drug therapeutics


1.4.1


Prednisone


Since 1985, Dalakas highlighted the immunologic and inflammatory component in the pathophysiological process of PPS . This author tested high doses of Prednisone (80 mg/d for 4 weeks with progressive decrease, for a total 12-week duration) but reported no improvement on fatigue or muscular strength ( Table 2 ).



Table 2

Expected efficacy of drug therapeutics and PPS.




























































Medications/Authors Study type # subjects Quality of life improvement Decrease in the sensation of fatigue and pain relief Muscular strength
Prednisone Randomized, controlled, double-blind 18 Not studied No significant difference No significant difference
Pyridostigmine Multicenter, randomized, controlled, double-blind 126 No significant difference No significant difference No significant difference
Pyridostigmine Randomized, controlled, double-blind 67 Not measured No significant difference No significant difference
Immunoglobulin Multicenter, randomized, controlled, double-blind 142 Significant improvement (SF36, p = 0.042) No significant difference Mean difference of 10% for the treated group
Immunoglobulin Not controlled 14 Not measured Mean VAS goes from 6 to 2/10, no efficacy on fatigue No significant difference
Coenzyme Q10 Controlled 14 Not measured Not measured No significant difference
Coenzyme Q10 Randomized, controlled, double-blind 7 No significant difference No significant difference No significant difference


1.4.2


Immunoglobulin


The use of immunoglobulin is supported by the same argument of an immune-related inflammatory disruption. Gonzalez et al. published the first study testing an immunoglobulin treatment (30 mg/d, 3 days in a row, repeated again after 3 months) versus placebo in 142 patients with PPS. They reported a difference in muscular strength of 8.6% between the two groups at the end of the study in favor of the treated group (+2.3 for the treated group vs −6.3 for the placebo group, p = 0.029). The scores in the areas of vitality and quality of life (SF-36) are significantly improved ( p = 0.042) as well as those for the ability assessment scale. This work emphasizes the idea of an inflammatory immune-mediated mechanism underlying the onset of PPS. Farbu et al. tested the immunoglobulin treatment on 20 PPS patients and did not find any benefits on muscular strength. However, the cohorts could not be compared (20 versus 142) to the ones of Gonzalez et al. However, Farbu et al. reported an improvement on muscle pain (mean VAS going from 6 to 2/10). Finally, in the arguments to support immune modulating therapy, a final study from Fordyce et al. showed a correlation between an increase in TNF-α protein or other harmful cytokines and the onset of PPS. Other ongoing studies are trying to establish specific biological criteria for PPS .


1.4.3


Pyridostigmine


Pyridostigmine has been one of the active drug component to be a candidate for treating PPS. This medication is capable of improving the transmission of nerve-muscular fibers (at the neuromuscular junction or motor plate), and it also has an impact on the in situ regeneration of terminal axonal endings of motor units. It promotes the coupling of nerve/muscle transmission but is also capable of stimulation growth hormone secretion, somatomedin C (SmC), hormone known for modulating the degenerescence/regeneration of the motor plates. Some studies have tried to validate a pyridostigmine treatment, but they were weakly positive in open studies and negative for controlled studies if we focus on the improvement of muscular strength. Trojan et al. have evaluated the efficacy of pyridostigmine on a dosage of 180 mg/d for 14 weeks and did not report any significant improvement on quality of life, muscular strength or fatigue after 6 months. Horemans et al. proposed a higher dosage (240 mg/d for 6 months) but their results showed a slight improvement in the strength of motor units not affected by the virus. Finally, the onset of PPS does not seem to be correlated to an SmC modulation deficit, however, no rigorous study was conducted on hypothalamus growth hormone axis in these patients.


1.4.4


Coenzyme Q10


The use of coenzyme Q10 (CoQ10) is based on a correlation between PPS and a decrease in the mitochondrial activity in the muscle groups of affected patients. Coenzyme Q10 has been tested for its positive and stimulating action on the enzymes of the mitochondrial respiratory chain (aerobic) and its protecting antioxidant properties. The studies are rare and the results deceiving whether CoQ10 is used alone (not controlled study, 100 mg/d for 6 months) or associated with a muscle strengthening program (randomized, controlled, double-blind study) 200 mg/d, in two daily takes over a 12-week period .


1.5


Conclusion


The therapeutic procedures for PPS lack some clinical standards. The medication therapeutics showed some pain-relief efficacy and a slight improvement on muscular strength and/or health-related quality of life assessments. If a single use of these medications remains limited, the association of this therapeutics (immunoglobulin plus physical therapy) could be a promising future therapeutic solution for PPS patients.




2


Version française


2.1


Introduction


La poliomyélite antérieure aiguë ou maladie de Heine-Medin correspond à une attaque infectieuse du motoneurone par le Poliovirus (groupe des Enterovirus à ARN du Picornavirus ).


Avant l’avènement de la vaccination, plus de 600 000 enfants par an ont été touchés dans le monde. Les dernières incidences les plus terribles (pandémie) sont survenues dans les années 1950. C’est une maladie infectieuse du système neurologique la plus pourvoyeuse de handicap moteur dans le monde : 55 000 patients avec des séquelles de poliomyélite en France, 700 000 en Europe, 20 millions dans le monde . À distance de cette pandémie virale et au moins 15 ans après une attaque par le Poliovirus , il est décrit chez certaines personnes infectées une modification de la symptomatologie. Les différentes études et la mise en commun des suivis longitudinaux de cohorte ont permis d’identifier une entité nosologique : le syndrome post-polio (SPP) . Des critères diagnostiques ont été définis. Aucun examen complémentaire n’est capable aujourd’hui d’identifier formellement ce syndrome. Selon les études, la fréquence de ce syndrome est estimée entre 20 et 60 % sans compter les conséquences psychologiques liées au passé de cette infection virale . Une fois le diagnostic posé, il reste à définir une thérapeutique adaptée au SPP. Ce travail est une revue de la littérature portant sur les procédures thérapeutiques utiles et leur efficacité attendue pour traiter les malades avec un SPP.


2.2


Syndrome post-polio, critères diagnostiques


2.2.1


Critères diagnostiques du SPP


Plusieurs auteurs ont proposé des critères diagnostiques. On retrouve constamment une triade clinique comprenant fatigue, douleur et extension de l’atteinte motrice. Cette symptomatologie non spécifique doit être précisée et nous retiendrons ici les critères diagnostiques d’Halstead et al. validés par un collège d’experts internationaux :



  • •

    histoire certaine de primo-infection par le Poliovirus avec une atteinte motrice initiale ;


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    récupération complète ou partielle (pouvant s’étendre sur plusieurs années) suivi ;


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    d’une période de stabilité neurologique et/ou fonctionnelle supérieure à 15 ans ;


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    perte rapide ou graduelle de l’endurance et/ou de la force musculaire avec ou non une atrophie musculaire dans des territoires auparavant cliniquement sains, associée à une fatigue généralisée musculaire et articulaire, une intolérance au froid ;


  • •

    cette symptomatologie se distingue par son caractère inhabituel et durable (évoluant depuis plus d’un an). D’autres symptômes plus rares peuvent être notés (anomalie du sommeil, difficultés respiratoires, dysphagie, dysarthrie, fasciculations, déformation des articulations).



Le SPP est un diagnostic d’élimination ( Tableau 1 ) : il faut systématiquement écarter toutes les causes médicales ou chirurgicales alternatives, pouvant être responsables de ces différents symptômes non spécifiques avant de poser le diagnostic SPP. L’existence même de cette entité nosologique a été discutée et controversée : évolution naturelle ou pathologique ? Nous citerons ici l’étude de Munin et al. qui ont effectué un suivi de patients poliomyélitiques sur trois ans. Ils ont évalué tous les six mois la force musculaire quadricipitale en isométrique et en isocinétique sans retrouver de diminution significative de la force (étude contrôlée). Ainsi, l’histoire naturelle de la poliomyélite n’évolue pas forcément vers une aggravation ou une extension de l’atteinte motrice. Comment explique-t-on la physiopathologie du SPP ?


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Apr 23, 2017 | Posted by in PHYSICAL MEDICINE & REHABILITATION | Comments Off on Post-polio syndrome: Pathophysiological hypotheses, diagnosis criteria, medication therapeutics

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