Control of breathing in systemic sclerosis

Systemic sclerosis (SSc) is a rare, systemic connective tissue disease
characterized by widespread microvascular damage and by increased production
and deposition of extracellular matrix components both in the skin and internal
organs. Autoimmune serological abnormalities and autoantibodies production are
common and the clinical presentation can differ widely for the extent and
localization of visceral damage (Black CM et al. 1993, Anderson N et al. 2002).
The involvement of the nervous system is usually limited and more often
localized in peripheral structures (Gordon RM et al. 1970). The unusual
occurrence of cerebral lesions has previously been interpreted as a
complication of microvessel defects in the presence of hypertension or renal
failure, or linked to antiphospholipid immunity or vasculitis (Averbuch-Heller
L et al 1992; Patahak R et al 1991).

In a recent study, macro- and micro-angiopathy was shown in brains of 16
patients with limited and diffuse asymptomatic SSc by using transcranial
Doppler ultrasonography (Giuliodori G et al 2009). This is a non-invasive
method to measure continuously the mean flow velocity in the middle cerebral
arteries. Using another imaging modality, brain MRI, hyperintensive lesions
(white matter abnormalities) were detected, including the brain stem, in
limited and diffuse SSc patients (Sardanelli F et al 2005; Mohamed RH et al
2010). In addition, Terrier and coworkers found an association between cerebral
vasculopathy and ischemic events in patients with limited and diffuse SSc
(Terrier B et al 2009).

In SSc, hypercapnic respiratory failure involves several factors (Nageh TT et
al 1998; Pugazhenthi et al 2003). First, it has been suggested that an
inability of respiratory muscles to sustain tension can develop as increased
respiratory resistance due to skin involvement of the thorax. Second, a gradual
down-regulation in cerebral central respiratory sensitivity for carbon dioxide
may occur as a result of slightly chronic elevated arterial partial carbon
dioxide pressure or a high normal partial carbon dioxide pressure. However, the
contribution of central and peripheral chemoreceptors, which regulate carbon
dioxide levels in a negative feedback loop, to hypercapnic respiratory failure
in these patients is unknown.

The normal ventilatory response to carbon dioxide is mediated by central and
peripheral chemoreflexes with chemoreceptors located in the carotid and aortic
bodies and the ventral medulla (Dejours P 1962). Many factors influence the
chemoreceptor response and thereby the control of breathing (Patrick J 1972).
To measure the ventilatory response to carbon dioxide and thereby estimating
the sensitivity to carbon dioxide a rebreathing method can be used (Read DJC
1967).

In daily care for our patients with SSc, we experienced several cases of
intercurrent hypercapnic respiratory failure, without known interstitial lung
disease or impaired diaphragm function. In our view, carbon dioxide retention
in these patients could not just be explained by a pneumonia or heart failure.
In these patients the central chemoreflex drive could be involved and altered
in the course of the disease. In addition, we speculate that the occurrence of
cerebrovascular lesions in the brain stem may be related to an altered response
of central chemoreceptors (Sardanelli F et al 2005; Mohamed RH et al 2010).

Recently, a study on the relation between neuropsychocological disorders and
chronic inflammation in cerebral metabolism in systemic sclerosis started in
the Leiden University Medical Center (P11.148). Apart from various
questionnaires, a brain MRI including the brain stem will be obtained.

Based on the above we hypothesized that the central chemosensitivity is altered
in patients with systemic sclerosis and neuropsychological disorders and is
associated with the presence of hyperintensive lesions (white matter
abnormalities) as is shown previously in systemic sclerosis.

Therefore we aim to investigate the respiratory drive by assessing the central
chemosensitivity and measurements of mouth occlusion pressures in all patients
participating in the P11.148 study.

-To assess the central chemosensitivity by an carbon dioxide rebreathing test
-To assess mouth occlusion pressures during the carbon dioxide rebreathing test
-To study the relation between these results and the results obtained with the
MRI and neuropsychological questionnaires (protocol P11.148)

Patients who participated in the MRI study (protocol P11.148) will be invited
to participate in the present study. This is a cross-sectional, explorative,
single center
case control study to assess the respiratory drive. Partners of patients with
systemic sclerosis will be invited to the present study as healthy matched
controls.

Participation will include 60 minutes of lung function measurements. Possible
side effect of the measurements could be a light headiness, diminishing in a
few minutes.