Neurotoxicity due to dimethylamine borane poisoning via skin absorption: a case report

Guang-cai Yu, Ya-qian Li, Tian-zi Jian, Bao-tian Kan,3, Si-qi Cui,3, Ping Han, Xiang-dong Jian,4

1Department of Poisoning and Occupational Diseases, Emergency Medicine, Qilu Hospital of Shandong University,Cheeloo College of Medicine, Shandong University, Jinan 250012, China

2 Shandong University of Traditional Chinese Medicine, Jinan 250012, China

3Department of Geriatric Medicine, Qilu Hospital of Shandong University, School of Nursing, Cheeloo College of Medicine,Shandong University, Jinan 250012, China

4School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China

Dear editor,

Dimethylamine borane (DMAB, CAS no. 74-94-2), also called boron-dimethylamine complex, is a white crystalline solid. It has an amine odour under mild conditions.[1]As an excellent reducing agent,DMAB is widely used in the semiconductor industry,pharmaceutical manufacturing,[2]oligomer and polymer production, and hydrogen storage.[3]Acute DMAB exposure may cause eye or respiratory irritation,throat discomfort, vomiting, diarrhoea, and pulmonary oedema.[1,4]Isolated reports indicated that DMAB exposure causes acute cerebellar oedema and peripheral neuropathy.[1,5,6]Herein, we report a case of DMAB poisoning via dermal absorption in which the central and peripheral nervous systems were the primary sites of toxic injury. We highlight the use of brain magnetic resonance imaging (MRI) and electromyography (EMG)for evaluation after exposure.

CASE

A previously healthy 32-year-old male operator at a pharmaceutical plant accidentally sprayed liquid DMAB over his work trousers. He experienced no immediate discomfort and continued working for another three hours, after which he took a shower and changed his clothes. Shortly thereafter, he developed dizziness,nausea, blurred vision, generalized weakness, and slowness in his movements. After a short break, the patient began vomiting and exhibited slurred speech,disrupted concentration, and ataxia. He was admitted to a local hospital 6 h after exposure; glucocorticoids,neurotrophic agent, and symptomatic therapies were administered. Despite intervention, the weakness increased progressively, and he developed numbness and pain on his legs 12 h after exposure. Approximately 35 h after exposure, bilateral lower limb weakness worsened until he could no longer ambulate. MRI revealed abnormal signaling on the bilateral dentate nucleus and the posterior limb of the internal capsule (Figure 1). The findings of brain magnetic resonance angiography were normal.

The patient was transferred to our department 69 h after exposure because of clinical deterioration.Upon admission, his consciousness was unimpaired,and his vital signs were stable. However, he had lower extremity weakness graded 2/5 (manual muscle testing,MMT), and he claimed a “prickling sensation” in his lower limbs. His temperature, pain, vibration, and touch sensations were intact. Although there was no weakness in the upper extremities, the finger-to-nose test indicated impairment. On admission, the results of his blood cell count, myocardial enzyme, electrolyte,coagulation, and hepatic and renal function test were unremarkable, except for a elevated creatine kinase (CK),which was 311 U/L (normal range 55-170 U/L). DMAB poisoning was considered based on the exposure history.Initial treatment for DMAB toxicity primarily includes administering mecobalamin (0.5 mg, 3 times per day,orally), vitamin B1 (100 mg/d, intramuscular injection),mouse nerve growth factor (30 μg/d, intramuscular injection), betamethasone (8 mg/d, intravenous drip), reduced glutathione (18 g/d, intravenous drip),nalmefene (0.1 mg, twice per day, intravenous injection),nadroparin calcium (4100 U/d, subcutaneous injection),and salvianolate injection (Chinese Medicine Approval:Z20110011, Tianjin Tasly Pride Pharmaceutical Co.,Ltd., China).

Five days after exposure, the muscle strength of the lower extremities decreased to grade 1/5, and the patient reported intolerable pain and disrupted sleep.His upper limb muscle strength and sensations were normal. His CK and lactic dehydrogenase (LDH) levels were 174 U/L and 217 U/L (normal range 120-230 U/L), respectively. Diclofenac sodium (75 mg, twice per day) was administered orally. Six days after exposure,the patient still had intolerable pain in both lower limbs.His electroencephalogram (EEG) revealed background diffuse low amplitude slow waves, indicating moderate diffuse cerebral dysfunction. His EMG revealed axonal polyneuropathy with predominant motor nerve involvement in both lower limbs.

Nine days after exposure, the patient’s leg pain was ameliorated, and the proximal and distal portions of the bilateral lower extremities were graded 4/5 and 3/5, respectively. The patient’s CK and LDH levels were 246 U/L and 237 U/L, respectively. Abnormal hyperintensities were noted on T2-weighted imaging(T2WI), fluid-attenuated inversion recovery (FLAIR),and diffusion-weighted imaging (DWI). There were also abnormal hypointensities on T1-weighted imaging(T1WI) at the bilateral cerebellar dentate nuclei (Figure 2). Additionally, abnormal signals were seen on the right head of the caudate nucleus, and magnetically sensitive material deposition was considered. However, whole spinal cord imaging was unremarkable.

Figure 1. MRI of a 32-year-old man at 35 h after dimethylamine borane exposure. The image shows hypointense lesions on T1WI (A and E), hyperintense lesions on T2WI (B and F) and FLAIR (C and G), and isointense and hyperintense lesions on DWI (D and H) at the bilateral cerebellar dentate nuclei and left posterior limb of the internal capsule. T1WI: T1-weighted imaging; T2WI: T2-weighted imaging;FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging.

Figure 2. MRI of a 32-year-old man at 9 d after exposure. The image shows hypointense lesions on T1WI (A and E) and hyperintense lesions on T2WI (B and F), FLAIR (C and G), and DWI (D and H)at the bilateral cerebellar dentate nuclei. An abnormal signal is also observed on the right head of the caudate nucleus. Magnetically sensitive material deposition was considered. T1WI: T1-weighted imaging; T2WI: T2-weighted imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging.

Fifteen days after exposure, the patient could ambulate with assistance, but prominent weakness and ataxic gait were evident. MRI revealed that the cerebellar dentate nuclei lesions had subsided, but the caudate nucleus lesion remained unchanged. EMG after another 2 d showed axonal polyneuropathy with motor and sensory nerve involvement in both lower limbs.EEG revealed poor background, low amplitude, and few diffuse low amplitudeθwaves indicative of mild diffuse cerebral dysfunction. Despite the persistent difficulty in ambulation, there was a slight improvement in the patient’s lower limb strength at 23 d after exposure.He was discharged with a prescription of vitamin B1,mecobalamin, and sodium diclofenac to be taken orally.He was also advised to undergo rehabilitation.

At 62 d after exposure, the patient’s lower limb pain and sensory impairment improved, but motor impairments worsened. Difficulty in ambulation and poor balance persisted. Muscle wasting was also observed,especially in the distal lower limbs. The EMG and MRI results remained unchanged. At 146 d after exposure,the patient’s lower extremity weakness and ability to ambulate had improved, which was now reflected in his EMG results. However, his gait was still clumsy. At 345 d after exposure, the patient’s lower extremity weakness further improvement and could walk normally, but still difficult to squat and rise.The patient’s EMG data are shown in Table 1.

Table 1. Results of nerve conduction studies in acute dimethylamine borane (DMAB) intoxication

Field occupational history investigation

The staff at the patient’s workplace cooperated with our investigation, and relevant information was obtained from the company. His workshop only produces DMAB,and the incident occurred at the end-product transmission pipeline, which produces 10% (w/v) DMAB. Three hours after exposure, after the patient had changed his clothes,his trousers were noted to contain white crystalline material. The raw materials used in he manufacturing process included tetrahydrofuran (C4H8O), potassium borohydride (KBH4), dimethylamine (C2H7N),phosphoric acid (H3PO4), and sodium hydroxide (NaOH).

DISCUSSION

DMAB is a direct neurotoxicant, exposure to which can lead to acute cerebral and cerebellar dysfunction and polyneuropathy. Tsan et al[1]reported a 36-year-old man whose face and trunk were exposed to DMAB spray.Subsequent damage to the cerebellar dentate nuclei was confirmed using MRI at day 8, which was noted to subside at day 37. Polyneuropathy was confirmed at day 29 after exposure. In our case, DMAB toxicity resulted in highly progressive central and peripheral nervous system injury. We confirmed cerebellar dentate nuclei damage and polyneuropathy at 35 h and 5 d following DMAB exposure, respectively. The mechanism of DMAB poisoning has not been demonstrated despite several case studies.

Toxic encephalopathies may involve cerebellar dentate nuclei.[7,8]Reversible acute cerebellar toxicity(REACT) is a rare encephalopathy that is associated with exposure to several chemotherapeutic and opioid agents.[9]Osmotic demyelination syndrome, commonly involving the central pons and other brain regions,hyponatraemia, and other factors are important.[10,11]In this case, bilateral cerebellar dentate nuclei lesions were found on T1WI, T2WI, FLAIR, and DWI. While transient demyelination, cerebal oedema, or neuronal damage could have cause these lesions, we suggest REACT was the most likely cause.

Toxic neuropathies, including those caused by organophosphates, acrylamide, platinum derivates, and n-hexane, can result in axonal neuropathy.[11]In this case, DMAB-induced polyneuropathy was considered as acute, consistent with the findings of Huang et al.[5]On EMG, the patient’s motor nerve function demonstrated a significant decline in amplitude and a mild decline in nerve conduction velocity, suggesting primary axonal damage. Conversely, sensory nerve function significantly declined in terms of nerve conduction velocity, indicating myelin damage. Huang et al[5]studied sural nerve biopsy specimens and found that DMAB-related peripheral nerve injury is very similar to triorthocresyl phosphate,n-hexane, and carbon disulphide neuropathies. Despite nutritional neurotherapy treatment for more than 3 months, motor nerve injury in the patient’s lower limbs showed no notable amelioration. Kuo et al[6]conducted a follow-up with the patient who was reported by Tsan et al[1], indicated that muscle strength and sensory functions in the feet were still abnormal one year after the exposure. Therefore, persistent polyneuropathy is one of the most important concerns in DMAB poisoning. Aside from nervous system injury, the patient in this report did not exhibit other signs of organ damage, consistent with previous reports.

DMAB can be easily absorbed through the digestive tract and intact skin, where tissue/blood ratios are low; DMAB accumulates most in the kidney and liver and is mainly excreted in the urine.[1,12]The LD50of DMAB to rats and mice is reportedly 39/59 mg/kg(intraperitoneal/oral) and 200/56 mg/kg (intraperitoneal/oral), respectively.[12]There is no specific antidote for DMAB poisoning. For dermal toxicity after exposure,prompt decontamination is necessary for effective treatment. Furthermore, DMAB becomes stable after absorption, with relative molecular weight of 58.9,and is mainly excreted via the kidney;[12]therefore,haemodialysis or hemofiltration may be used for emergency treatment in early stages. Trophic nerve therapy and rehabilitation exercises are conventional methods for managing DMAB-related nervous system injury. The initial treatment for this patient, except for trophic nerve therapy, we also used nadroparin calcium and salvianolate injection to improve microcirculation .

CONCLUSION

DMAB is a direct neurotoxicant that can be absorbed through the skin, resulting in transient cerebellar dentate nucleus region damage and persistent peripheral neuropathy. In peripheral neuropathy, motor nerve axonal injury and sensory nerve distal demyelination are the main long-term clinical feature and a barrier to treatment.

Funding:Scientific Research Project of Qilu Hospital, Shandong University (project no. KYLL-2019-296).

Ethical approval:This study was approved by the Ethics Committee of Shandong University of Qilu Hospital.

Conflicts of interest:The authors declare that there are no conflicts of interest.

Contributors:GCY conceived the study, drafted the manuscript,and take responsibility for the paper as a whole; all authors contributed substantially to its revision. PH and XDJ chaired the data oversight committee.