Introduction - Uppsala Monitoring Centre

‘By far the most important toxic effect was the damage to the
vestibular apparatus. Giddiness was a frequent first symptom; it was
noticed by 36 of the 55 patients, and first appeared on sitting up in
bed or turning the head suddenly. It appeared usually in the fourth or
fifth week of therapy, and persisted for periods varying from one
week to several months. Spontaneous nystagmus on lateral vision
was another frequent sign of vestibular disturbance; blurring of vision
was less common. Tests for vestibular dysfunction were not carried
out in all centres with sufficient regularity and uniformity to permit
analysis of grouped results, but it is possible to say that absence or
reduction of caloric response was not found with the frequency
reported in many American investigations, and that in some patients
loss of response was temporary only. No standard functional tests at
the ends of treatment were performed; many patients are reported as
having unsteadiness of gait, which improved gradually with visual
compensation but remained a handicap in the dark, crossing a
congested street, or walking in a moving train. It is highly desirable
that standard tests be adopted for assessment of vestibular
dysfunction. No loss of hearing was reported, except for two cases of
high-tone deafness.’ (MRC Council, 1948).
Comment: there was no comparison with the control group as far
as adverse effects were concerned; no information on grouping of
symptoms; many adverse events have no numbers attached; no
comparison with previous studies in the discussion section; no
grading of severity (MRC, 1948). The clinical trial form (A) requested
symptoms on admission and these included vertigo, giddiness and
deafness (These had already been established as ADRs in the
USA). This form also asked for ‘Previous treatment for present illness
(dates, place, nature and duration of treatment)’, but no request for
details of treatments for other illnesses. The final summary form (A3)
had space for ‘Evidence of toxicity’ and remarks, so that it presumed
that the investigator’s opinion as to attribution was correct. Form (C)
Clinical Record said ‘Record here symptoms and clinical findings not
recorded on sheets A or B. Symptoms attributable to streptomycin
toxicity should be underlined.’ Form (D) was a record of treatment.
Although vestibular disturbance and deafness were predictable
insufficient testing was performed to allow a true assessment of the
damage done. No analysis of the reversibility of these ADRs was
published. In 1951 a paper on the return of the vestibular function
following streptomycin toxaemia was published. Of 62 patients who
had taken 2 gm daily for 110 days: 42 had complete loss of caloric