The case presented here showed suggestive evidence linking the drug to the event. To associate bortezomib to the oculomotor nerve palsy, we had to rule out all other possible causes, assess the temporal relationship and pharmacological time plausibility, and confirm positive dechallenge/rechallenge response.
Our patient's only known comorbidities are hypertension of ten years duration controlled by enalapril and atenolol, and open angle glaucoma of two months duration controlled by latanoprost eye drops. These three medications (enalapril tablets, atenolol tablets and latanoprost eye drops) are not reported to cause oculomotor nerve palsy or any other similar cranial nerve palsy or neuropathy. Furthermore, she had used enalapril tablets and atenolol tablets for ten years and latanoprost eye drops for two months without developing this adverse event. She has no past history of any cerebrovascular accident or any thromboembolic event. She is not known to be diabetic and not known to suffer from peripheral vascular disease. She never complained of any similar incident of cranial nerve palsy or even peripheral neuropathy.
Fundoscopy was carried out and it showed the optic disc to be within normal appearance, no papilloedema was detected. A beta scan of both eyes was done and showed bilateral normal retinochoroidal thickness and bilateral normal optic nerve thickness.
Magnetic resonance imaging (MRI) of the brain and brain stem with and without contrast was carried out and the only finding was a focal enhancing area in the white matter of the right pons about 11 mm in maximum diameter with low T1 and high T2 signal. This area showed diffuse enhancement in the post contrast study and there is no surrounding edema detected. This was graded as a non-specific appearance and differential diagnosis includes demyelination and minute cerebrovascular accident. A decision was taken not to follow this non-specific lesion by a repeat MRI of the brain and brain stem since this lesion is right sided and usually left oculomotor nerve palsy is expected to occur by an ipsilateral structural lesion on the same side.
Cerebrospinal fluid (CSF) was obtained by lumbar puncture. Cytological examination of the CSF sample was negative for malignant cells. An analysis and cell count of the CSF sample showed negative criteria for subarachnoid hemorrhage, multiple sclerosis and/or viral and bacterial meningitis. Glucose level in the CSF sample was 4.4 mmol/L (reference range: 2.2 to 3.9), the protein level in the CSF sample was 440 mg/L (reference range: 120 to 600). The CSF sample total volume was 1.3 mL, with clear appearance and was colorless, white blood cell count in the sample was three cells per microliter (reference range: zero to five) and red blood cell count in the sample was zero cells per microliter (reference range: zero to five). CSF culture and sensitivity showed no growth after 72 hours of incubation and no growth after enrichment culture.
Nerve conduction studies were not done because although our patient complained of numbness and peripheral paraesthesia, they were mild and did not interfere with the activities of daily living.
Despite the CSF cytology being negative for malignant cells and a MRI of the brain being inconclusive, it is impossible to rule out with 100% certainty extramedullary myelomatous infiltration of the brain. The only point that suggests that this adverse event wasn't related to multiple myeloma was that the serial serum IgG level which was used as a biomarker to follow the status of her disease was dropping from baseline of 53.4 g/L before initiation of the bortezomib to 23.5 g/L on the day she developed this adverse event meaning that her disease was responding to bortezomib.
This is a plausible collateral adverse event that occurred early as regards time onset. Our patient was on bortezomib (1.3 mg/m2
; total dose of 2 mg) as a first line monotherapy that was administered as intravenous push once weekly, she received Cycle 1 week 1 (Day one), Cycle 1 week two (Day eight), Cycle 1 week three (Day 15) and developed the adverse event on Cycle 1 Day 21. According to the DoTS classification, this is probably a collateral effect of early persistent or intermediate time-course; the susceptibility factors are not known [1
To the best of our knowledge, there has been no previously reported or published recognized association (oculomotor nerve palsy) or even similar association (cranial neuropathy) with the product 'bortezomib' or the class 'proteasome inhibitor'. There have been several reports of peripheral neuropathies with the product 'bortezomib' or the class 'proteasome inhibitor'.
Plasma level of bortezomib or its metabolite was not assessed at the time of the adverse event.
There is insufficient animal and in vitro data regarding the association of cranial nerve palsy with bortezomib as a possible adverse event related to the drug.
Omitting Cycle 1 week four (Day 22) of bortezomib resulted in partial improvement of the signs of oculomotor nerve palsy. Partial improvement was noticed on Cycle 1 Day 27 i.e. after five days of omitting the dose of bortezomib.
Giving cycle 2 week one (Day one) of bortezomib resulted in reappearance of most of the signs of left sided oculomotor nerve palsy after 48 to 72 hours of reintroducing bortezomib.