MS

Journal of Hyperbaric Medicine, Vol. 5, No.4, 1990

Long-term Hyperbaric Oxygen in Multiple Sclerosis:

A Placebo-controlled, Double-blind Trial With Evoked Potentials Studies

G. Oriani, S. Barbien, G. Cislaghi, G. Albonico, G. Scarlato, C. Mariani, and C. Pirovano

Institute of Clinical Neurology University of Milan and Istituto Ortopedico Galeazzi, Milan, Italy

Oriani G, Barbieri S, Cislaghi G, Albonico G, Scarlato G, Mariani C, Pirovano C. Longterm hyperbaric oxygen in multiple sclerosis: a placebo-controlled, double-blind trial with evoked potentials studies. J Hyperbaric Med 1990, 5(4):237-245. In several studies, hyperbaric oxygen (HBO) has demonstrated an immunosuppressive action in allergic encephalomyelitis and other pathologies. Since 1970, several investigators have tested this activity in multiple sclerosis (MS). Inasmuch as MS is a chronic, well defined pathology, we applied prolonged HBO therapy to evaluate its therapeutic value. Here we present our double-blind, randomized study on 44 patients with a clinically defined MS group Al. The effects of prolonged HBO therapy were evaluated by means of clinical and neurophysiologic investigations; one year of therapy and one year of control.

Introduction

The irnunosuppressive action of hyperbaric oxygen (HBO) has been proved with experimental studies in allergic encephalomyelitis and other pathologies (1-3). Since 1970, clinical studies, most of them uncontrolled and not blind, have been set up to evaluate the possible efficacy of HBO in patients with multiple sclerosis (MS).

The results have been controversial: Some trials reported a positive action of HBO (4-11) whereas others have shown no clinical improvement (12-23). Since clinically definite MS is a chronic disease, it is not reasonable to assess the efficacy of any therapy on the basis of a short-term treatment, as has been done in most of the previous studies (4-20, 22); only in the trial of Harpur et al. (21) did treatment last 6 mo., with seven "booster" exposures.

In this paper the effects of prolonged HBO therapy have been evaluated by means of both clinical and neurophysiologic investigations in a selected population of 44 patients with clinically defined multiple sclerosis group Al (CDMSA1) according to Poser et al. (24).

Methods

Patients

Forty-four patients with CDMSA1, with a duration of the disease of more than 10 yr and an expanded disability status scale (EDSS) (25) score lower than 5, were considered for the study. None of the patients had an exacerbation of the disease during the 6 mo. before the start of the study. Treatment with steroids or immunosuppressants was allowed only if patients were receiving one of these compounds regularly for more than 6 mo. (steroids) or 12 mo. (immunosuppressants). No new drugs were permitted and all patients were asked to maintain their customary habits.

Patients with contraindications to HBO therapy, such as active pulmonary disease, glaucoma, otitis, sinusitis, seizure disorder, or abnormal EEG, were excluded. The purpose and execution of the trial were explained to each patient and informed consent was obtained. The trial protocol was approved by the Ethical Committee of the hospitals. The treatment was free, and the study was not supported by any company or institution. All patients were randomly allocated to the treatment or placebo group. Both groups were matched with respect to age, sex, duration of the disease, and EDSS score (Table 1). The randomization code was known only to the chamber operator.

Treatment

A double-lock multiple chamber with constant temperature and humidity was used. Six patients were treated simultaneously. The HBO group received

Table 1: Characteristics of Patients

HBO Air

Number 22 22

M:F ratio 4:18 2:20

Age, yr

Mean 37.8 41.7

SD 14.4 13.8

Range, duration, yr (20-70) (l8-62)

Mean 14.5 11.9

SD 15.2 10.2

Range, EDSS score (2-56) (2-34)

Mean 3.39 2.97

SD 1.16 0.84

Range, FS~ score (2-5) (2-4.5)

Mean 6.84 5.78

SD 2.56 2.58

Range (3-10) (3-9)

100% oxygen at 2.5 atm abs delivered through a full face mask. The placebo group received a mixture of oxygen (20%) and nitrogen (80%) (air) at the same pressure. The therapeutic protocol used for both groups was an initial treatment of 90 min. for 5 days a week for 1 mo., followed by "booster" treatments of 90 min. for 5 days a week for 1 yr. Air was used to compress the chamber. The patients were breathing in a system that allowed the direct expulsion of respiratory gases. Air and oxygen piping leading systems were indistinguishable to the breathers. To avoid uncontrolled decrease of oxygen pressure, tightly adherent silicon masks were used and the partial pressure inside them was measured by means of a modified transcutaneous oxymeter (De Mori), found to be at 2.3 atm abs, with a decrease of less than 10% of the initial pressure delivered to the breathing circuit.

Clinical Evaluation

Before beginning the study, each subject was given a complete physical examination including an otologic and ophthalmologic evaluation. Neurologic examinations were independently performed by three neurologists. An initial assessment was performed immediately before treatment; three other assessments were made, one immediately after treatment and the other two, 6 and 12 mo. after the beginning of treatment. A quantitative evaluation of deep tendon reflexes and strength was used (26, 27), and EDSS and functional systems scale (FSS) were also adopted (25). At the end of the first month and at the end of the study the patients were required to complete a brief questionnaire which asked whether they thought they were better or worse.

Neurophysiologic Evaluation

Pattern-shift visual (PSVEPs), brainstem auditory (BAEPs), and somatosensory evoked potentials (SEPs) were studied just before the beginning of treatment, at the end of the first month, and at the end of the study (1 yr after the beginning of therapy). To rule out a possible direct effect of oxygen on the conduction along the CNS pathways, 2 groups of subjects were also investigated by means of a PSVEP study.

Group 1 was 10 patients affected by bone diseases (osteomyelitis, Sudeck's atrophy, etc.) who received HBO therapy for a period of 2-4 wk. Group 2 was 10 normal controls who volunteered for the study and who underwent a single, 90-min pure oxygen treatment. For both groups the pressure was maintained at 2.5 atm abs.

Results

All patients completed the study, and the problems related to pressurization were of minor importance, consisting mainly of ear discomfort and anxiety, particularly during the first treatment.

A significant reduction of the mean EDSS (P < 0.05) and of pyramidal and cerebellar functional system sc6re (P < 0.05) was evident in the HBO group after 1 yr of therapy. Furthermore, the number of improved patients was significantly higher (P < 0.05) in the same group at the end of the study (Table 2). If the number of patients with a decrease of the EDSS score of at least two points is considered, at the end of the year of treatment, 8 patients in the HBO group but none in the air group met this criterion (P < 0.01).

In Table 3 the EDSS score, FSS total score, and the score of each functional system of these patients are reported. The subjective evaluation of the patients through the questionnaire yielded the following results. In the HBO group, 14 patients reported a beneficial effect, 4 no variations of their clinical status, and 4 a worsening of their conditions. In the air group, 2 reported a beneficial effect, 11 no variation, and 9 a worsening of their conditions (P < 0.1).

A significant variation of the mean P100 latency (P <0.001) and of the latencies of BAEPs III and V waves (P <0.01 and P <0.05, respectively) was present in the HBO group after the first month of therapy and was maintained after 1 yr of treatment (Table 4). In the HBO group, individual changes in latencies alter treatment were small. In particular, using the criterion adopted by Matthews and Small (28) defining 10 msec as the minimum value for change of P100 latency to be taken into account, only6 patients with abnormal PSVEPs showed appreciable reduction in PSVEP latencies and only in 2 of those did latency return below the upper normal limit used in our lab (115 ms).

Discussion

We have found HBO beneficial to patients with CDMSA1 and adopting a statistical evaluation of the EDSS and FSS mean score changes as indices of clinical improvement after only 1 yr of treatment. Immediately after the first month of therapy and in the assessment at 6 mo., no significant variations of the scores were evident. This could partially explain why other studies do not report a beneficial effect (13, 14). In fact, in none of them was the treatment and the follow-up prolonged up to 1 yr. We believe that some important points must be addressed before dismissing HBO therapy and considering it useless in treating a disease for which no other treatment has been proved to be very effective. We agree with other authors (19,23) that It would be possible for patients to experience appreciable benefit without showing a change in the EDSS and FSS score, because in these particular cases, where minor modifications are expected (slowing of the progression of the disease), Kurtzke's scale is probably not accurate enough (13).

Following the advice of Bates (23), we studied the number of patients in the 2 groups that genuinely gained benefit from the treatment under investigation (reduction of at least two points of the EDSS score) and found a significant difference (P < 0.01) (Table 3). Even if we do not consider that the number of improved patients is greater in the HBO group (Table 2), the subjective evaluation of patients by neurophysiologic investigations seems to indicate the efficacy of HBO on the CNS pathways.

Table 2. Follow-up of patients with EDSS and FSS Score (Mean Values) and Variations of their clinical status.

HBO Air

	1	2	3	4	1	2	3	4
FDSS score	3.39	3.44	3.01	2.71^a	2.90	3.07	2.89	2.76
FSS score	6.84	7.03	6.44	5.90	5.71	5.76	6.01	5.42
Pyramidal	2.58	2.38	2.16	2.09^a	2.38	2.38	2.04	2.06
Cerebellar	0.81	0.54	0.56	0.36^a	0.92	0.92	0.77	0.60
Brain stem	1.34	1.52	1.46	1.20	1.06	1.36	1.43	1.01
Sensory	1.27	1.83	1.83	1.43	0.96	1.09	1.27	1.06
Bowel and bladder	0.64	0.56	0.45	0.44	0.00	0.00	0.13	0.13
Visual or optic	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
Cerebral or mental	0.36	0.36	0.45	0.45	0.27	0.27	0.27	0.27

		1-2			1-3			1-4			1-2			1-3			1-4
	A	B	C	A	B	C	A	B	C	A	B	C	A	B	C	A	B	C
EDSS score	4	12	6	10	10	2	12	8	2^b	0	18	4	5	13	4	4	14	4
FSS score	4	8	10	8	8	6	9	8	7	4	12	6	6	12	4	9	9	4
Pyramidal	4	18	0	9	11	2	<