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some papers report acute dysautonomia involving the parasympathetic and sympathetic system , like a paraneoplastic syndrome , in hodgkin lymphoma and others describe improvements after the treatment of the disease .
some studies suggest that such autonomic changes are related to the malignant disease , but others claim that they are the consequence of chemotherapy .
given these conflicting findings , we tried to verify whether lymphoma per se or chemotherapy for this disease genuinely influence the autonomic system .
we considered two groups of patients with lymphoma : the first one was formed by subjects who had been cured , while the other one was constituted by cases still receiving treatment .
in a period of over one year , we studied 40 cases ( m 20 ; f 20 ; mean age 58.77.3 ) , 18 of them of non - hodgkin ( nh ) lymphoma and 22 of hodgkin ( h ) lymphoma , all attending our outpatients clinic for regular follow - up and/or treatment .
all the cured subjects had received both chemotherapy ( ct ) and external beam radiotherapy ( rt ) , the latest dose having been administered almost a year previously .
the current patients were still receiving combined ct ( including toxic agents such as vinca alkaloids ) and/or rt based on international protocols .
the control group was of 40 subjects ( m 20 ; f 20 ; mean age 59.56.7 ) ( table 1 ) . 

table 1general characteristics of hodgkin and non - hodgkin subjects and controls.hodgkin and non hodgking subjectscontrolsage ( years)58.77.359.56.7gender ( % males)50 % 50%diabetes mellitus1.6%2.4%hypertension2.4%3.2% 
  all subjects underwent to the autonomic evaluation .
subjects underwent cardiovascular autonomic nerve function tests , in the following order : deep breathing test , valsalva test , isometric hand grip test , laying to standing test and tilt test . in the deep breathing test ,
a test of vagal heart rate control , the duration of the expiratory and inspiratory breaths was 5 seconds each for a total of 40 seconds ( 4 respiratory cycles ) .
the ratio of the longest to the shortest respiratory rate ( rr ) intervals was determined from the ecg for each respiratory cycle , and the mean of the four ratios was taken as the expiratory / inspiratory ( e / i ) ratio . in the valsalva test , which measures both parasympathetic and sympathetic functions , subjects blew into a manometer , maintaining an intrathoracic pressure of 40 mmhg for 15 seconds .
the ratio between the shortest rr interval during the expiratory effort and the longest rr interval during the 20 seconds afterwards ( valsalva ratio ) was calculated . in the isometric hand grip test , subjects squeezed a dynamometer in their dominant hand for 3 minutes using a force corresponding to 30% of their maximal squeezing force .
heart rate and blood pressure were measured at rest , before and after gripping the dynamometer . in the laying to standing test
, subjects suddenly stood up after resting quietly in a supine position for 5 minutes .
heart rate and blood pressure were measured at rest and then 1 , 3 , 5 and 7 minutes after standing up . in the tilt test , subjects laid supine on an electric tilt table . a restraining strap , applying a negligible pressure to the surface of the body put across the upper abdomen , secured the patients to the tilt table during the upright tilt .
humeral blood pressure and electrocardiograms were recorded continuously throughout the test , which lasted 30 minutes and was judged to be positive only in the case of symptoms fully reproducing the patient 's original pre - syncopal or syncopal symptoms accompanied by arterial hypotension , bradycardia or both .
autonomic test results were compared using student 's two tailed t - test for matched data .
subjects underwent cardiovascular autonomic nerve function tests , in the following order : deep breathing test , valsalva test , isometric hand grip test , laying to standing test and tilt test . in the deep breathing test , a test of vagal heart rate control , the duration of the expiratory and inspiratory breaths was 5 seconds each for a total of 40 seconds ( 4 respiratory cycles ) .
the ratio of the longest to the shortest respiratory rate ( rr ) intervals was determined from the ecg for each respiratory cycle , and the mean of the four ratios was taken as the expiratory / inspiratory ( e / i ) ratio . in the valsalva test , which measures both parasympathetic and sympathetic functions
, subjects blew into a manometer , maintaining an intrathoracic pressure of 40 mmhg for 15 seconds .
the ratio between the shortest rr interval during the expiratory effort and the longest rr interval during the 20 seconds afterwards ( valsalva ratio ) was calculated . in the isometric hand grip test , subjects squeezed a dynamometer in their dominant hand for 3 minutes using a force corresponding to 30% of their maximal squeezing force .
heart rate and blood pressure were measured at rest , before and after gripping the dynamometer . in the laying to standing test
, subjects suddenly stood up after resting quietly in a supine position for 5 minutes .
heart rate and blood pressure were measured at rest and then 1 , 3 , 5 and 7 minutes after standing up . in the tilt test , subjects laid supine on an electric tilt table . a restraining strap , applying a negligible pressure to the surface of the body put across the upper abdomen , secured the patients to the tilt table during the upright tilt .
humeral blood pressure and electrocardiograms were recorded continuously throughout the test , which lasted 30 minutes and was judged to be positive only in the case of symptoms fully reproducing the patient 's original pre - syncopal or syncopal symptoms accompanied by arterial hypotension , bradycardia or both .
autonomic test results were compared using student 's two tailed t - test for matched data .
table 2 summarizes the results of the autonomic tests in current patients and cured subjects : the latter had no autonomic dysfunction , whereas current patients had altered deep breathing test results and valsalva ratios .
we also evaluated current cases and cured cases versus healthy subjects and we found that the autonomic evaluation was altered only in current cases , while cured patients did not differ from healthy ( tables 3 , 4 ) . 

table 2results of autonomic tests in the study groups ( current vs. cured patients).testparametercurrent pts ( n22)cured pts ( n40)deep breathinge
/ i ratio1.10.031.40.04*valsalva maneuvervalsalva ratio1.30.11.90.1*hand grip testdiastolic blood pressure increase in mmhg19.13.123.33.1laying to standing testsystolic blood pressure decrease in mmhg5.26.23.44.5tilt testrr intervals1.080.011.20.03*p<0.05 
 table 3results of autonomic tests in the study groups ( current patients vs healthy subjects).testparametercurrent pts ( n22)cured pts ( n18)deep breathinge / i ratio1.10.031.420.02*valsalva maneuvervalsalva ratio1.30.11.860.3*hand grip testdiastolic blood pressure increase in mmhg19.13.120.44.7laying to standing testsystolic blood pressure decrease in mmhg5.26.25.54.6tilt testrr intervals1.080.011.120.01*p<0.05 
 table 4results of autonomic tests in the study group ( cured vs. healthy subjects).testparametercured pts(n18)healthy(n40)deep breathinge / i ratio1.40.041.420.02valsalva maneuvervalsalva ratio1.90.11.860.3hand grip testdiastolic blood pressure increase in mmhg23.33.120.44.7laying to standing testsystolic blood pressure decrease in mmhg3.44.55.54.6tilt testrr intervals1.20.035.54.6
autonomic dysfunction is documented in cases of lymphoma , but it is important to clarify whether this is a paraneoplastic manifestation or a consequence of chemotherapy because , in the first hypothesis , chemotherapy can cure the alteration , while in the second one it may exacerbate the dysfunction , with all the well - known consequences .
in fact , autonomic impairment is responsible for a higher mortality rate due to cardiovascular disease , such as sudden death resulting from cardiac arrhythmia .
our study shows that dysautonomia in lymphoma is a direct consequence of the disease and that cured patients show no more signs of this alteration ; so they return to a normal state like control subjects . this result
is confirmed also by the fact that our subjects , even if treated with vincristine , did not manifested any neuropathy like pal reported .
however it could be possible that these changes depend on other factors different from chemotherapy .
the results confirm that autonomic changes in patients with lymphoma may represent a paraneoplastic disease .
we wanted to determine whether autonomic dysfunction in patients with lymphoma is related to chemotherapy or represent a paraneoplastic syndrome . 
 40 patients with current or cured hodgkin or non - hodgkin lymphoma and 40 healthy controls , matched for age , gender , hypertension and diabetes mellitus underwent autonomic evaluation ( deep breath , valsalva maneuver , hand grip , lying to standing , tilt test ) . 
 current patients also suffering from diabetes or hypertension , or still on chemotherapy revealed autonomic changes , while cured or healthy subjects did not . 
 autonomic dysfunction in lymphoma is a transient manifestation of a paraneoplastic syndrome .