Peripheral hypoxia and autonomic responses in restless legs syndrome

Abstract

Syy levottomat jalat -oireyhtymään saattaa olla jalkojen hapenpuutteessa

Levottomat jalat -oireyhtymän syy saattaa aiemmasta tiedosta poiketen olla jalkojen hapensaannissa. DI Aaro Salmisen Tampereen yliopistossa tarkastettava väitöskirja osoittaa, että levottomista jaloista kärsivät potilaat kärsivät myös hapenpuutteesta jaloissaan.

Levottomat jalat -oireyhtymä on usein aliarvioitu vaiva, joka voi aiheuttaa vakavaa unihäiriötä siitä kärsiville potilaille. Siitä kärsivien potilaiden unensaanti vaikeutuu huomattavasti jaloissa ilmenevän levottomuuden ja epämiellyttävän tunteen takia, aiheuttaen päiväväsymystä. Levottomista jaloista kärsii jossain elämänvaiheessa Suomessa jopa 10 % väestöstä. Pahimmillaan se on raskauden aikana ja munuaishäiriöstä kärsivillä potilailla.

Yleisesti levottomien jalkojen alkuperän uskotaan olevan aivoissa. Salmisen väitöskirja kuitenkin haastaa tämän näkemyksen osoittamalla, että levottomista jaloista kärsivillä potilailla on jaloissaan matalammat happipitoisuudet kuin terveillä kontrollihenkilöillä. Tutkimuksissa jalkojen happipitoisuuden sai myös korjattua takaisin normaalitasolle levottomat jalat -oireen hoitoon käytettävällä lääkkeellä.

Salmisen väitöskirjan tulokset saattavat avata uusia väyliä levottomat jalat -oireyhtymän ymmärtämisessä. Jos teoria jalkojen happipitoisuuden osuudesta levottomien jalkojen synnyssä pitää paikkansa, se voi auttaa tulevaisuudessa uusien hoitomuotojen kehityksessä.

Restless legs syndrome (RLS) is a circadian disorder with both sensory and motor components. It is characterized by an uncomfortable feeling in the legs that typically occurs in the evening time at rest, and urges movement. It is a hereditary disorder that affects up to 30% of Western populations at some point in their lives, and requires medical attention in 2% of the population. RLS may appear independently of other medical conditions, or related to pregnancy or renal failure. Most patients with RLS also have periodic leg movements (PLM) during sleep. Dopaminergic medication alleviates RLS and suppresses PLM efficiently. The pathophysiology of RLS is currently not known. Most commonly, the origin has been suggested to be in the brain or spinal cord, but the findings have been slightly inconsistent. Therefore, other mechanisms have been suggested. Recent studies have demonstrated the activation of hypoxic pathways in the legs of RLS patients, suggesting peripheral involvement. However, the reason why these pathways are activated remains unknown. The aim of this work was to investigate potential hypoxia and hypercapnia in patients with RLS and the autonomic activations coupled to PLM. The partial pressure of oxygen and carbon dioxide (ptO2 and ptCO2, respectively) was investigated in the skin tissues of the legs of 15 RLS patients and 14 healthy controls during provocation of RLS symptoms. Transcutaneous measurements were used to estimate the partial pressures. Simultaneously, skin temperature, oxy-hemoglobin saturation (SaO2) and subjective discomfort were monitored. During the night, a polygraphic sleep study was performed to a subset of patients. The sleep study included recording of the plethysmogram signal from the toe in order to detect events of vasoconstriction. The patients with RLS showed lower oxygen levels in their legs (5.54kPa vs. 7.19kPa, p<0.01) but not on the chest (8.75kPa vs. 8.20kPa, p=0.355), when compared to the control subjects. The oxygen level was found to correlate with the severity of RLS. The skin temperatures or the levels of SaO2 or ptCO2 did not differ between patients and controls. During sleep, the PLM were associated with transient events of vasoconstriction in a subset of RLS patients. The administration of pramipexole raised the peripheral oxygen levels (from 5.54kPa to 6.65kPa, p<0.05) and suppressed PLM and vasoconstriction events. PLM were also investigated in a patient with a complete spinal cord injury with four polygraphic sleep recordings. The patient had a heavy burden of PLM at baseline. The PLM were temporally disconnected from the cortical and autonomic arousals. When a single dose of pramipexole was administered, the PLM were suppressed. The data presented here provides evidence that hypoxia may be the reason behind the activation of hypoxic pathways in the periphery of RLS patients. The hypoxia could have a role in the pathogenesis of RLS, suggested by the connection with RLS severity. However, the hypoxia is not likely to be caused by reduced blood flow, as indicated by the normal skin temperature. Evidence suggests that pramipexole redirects blood flow to the periphery and resolves the local hypoxia. This could be a potential new site-of-action of dopaminergic therapy. Regarding PLM, our data describes for the first time the transient peripheral vasoconstriction related to the leg movements. The effect of pramipexole implies that the vascular events are in tight causal relationship with the leg movements. On the other hand, it was shown that PLM may appear and may be suppressed by pramipexole without a connection to the brain. This suggests that the PLM in our patient are generated somewhere below the level of the lesion, either in the spinal cord or the periphery. In conclusion, this work provides further evidence supporting the involvement of peripheral systems in the generation of both RLS symptoms and PLM. Possible systems involved in the peripheral aspects of RLS are the autonomic nervous system, oxygen transportation, blood circulation or hypoxic pathways. Although consistent, the findings should at this point be considered preliminary and need to be confirmed in future studies.