Final Diagnosis

N-hexane-induced giant axonal neuropathy

Patient Follow-up

The patient was advised to avoid any route of exposure to leather cements at her work. She underwent physical and occupational therapy with her symptoms improved gradually. In a follow-up visit one and a half years later, she was able to walk on her own with mild residual numbness and tingling sensation. Examination showed mild residual distal limb weakness and sensory impairment as well as absent ankle jerks.

Discussion

N-hexane used as solvents in shoe, furniture, automotive, and printing industries as well as recreational glue/gasoline sniffing is neurotoxic [1–3]. Chronic n-hexane intoxication can result in sensory and motor axonal polyneuropathy with secondary demyelination [4, 5]. Rarely conduction blocks can be seen on the nerve conduction studies [6]. The neuropathy symptoms are often slowly progressive, but the disease onset can be insidious or subacute. Sensory symptoms are usually the initial complaints followed by muscle weakness with a pattern of distal predominance [5]. Paresthesias and dysesthesias are common, but pain is usually minimal. The development of neuropathy seems to have no direct relationship to the duration of exposure; hence, factors such as individual susceptibility may be important. Optic neuropathy and central nervous system (CNS) involvement are uncommon, and autonomic neuropathy is rarely encountered [2, 5]. The hallmark of the nerve pathology is segmental swelling of axons with thinning of the overlying myelin sheath without marked active nerve fiber degeneration or regeneration as seen in our case [1–6]. Electron microscopic (EM) examination of nerve biopsies often shows accumulation of packed intermediate neurofilaments [1–6], which is suggestive of disorganized network of cytoskeleton [1]. This may affect axonal transportation and other cellular functions, resulting in primary axonopathy. Aggregation of intermediate neurofilaments has been shown to impair mitochondrial motility with resultant metabolic and oxidative stress [7]. Ultrastructural studies of n-hexane neuropathy in the animal models showed that there was a retrograde, temporal spread of axonal swelling from distal paranodal sites and up along the affected nerve trunks, but the axonal degeneration did not begin in the nerve terminal or spread centripetally along individual nerve fibers; it was rather in a multifocal pattern [8, 9]. The exact pathogenic mechanism of n-hexane-induced GAN remains unknown. Nevertheless, n-hexane neuropathy shares these above-mentioned neuropathological features with the hereditary form of GAN [10–12].

Hereditary GAN is a rare, autosomal recessive, and progressive neurodegenerative disease seen in pediatric population. It is characterized by progressive motor and sensory peripheral neuropathy, CNS involvement with pyramidal and cerebellar signs, and characteristic kinky hair [10, 11]. In the hereditary form of GAN, the GAN gene mutations cause reduced or dysfunctional gigaxonin which is crucial for ubiquitin-proteasomal degradation of neuronal intermediate neurofilaments, resulting in accumulation of intermediate neurofilaments [12, 13]. In n-hexane-induced GAN, it has been postulated that n-hexane is converted to toxic gamma-diketone metabolite 2,5-hexanedione (2,5-HD), which can cause covalent crosslinking of neurofilaments, resulting in intermediate neurofilaments aggregation [14].

Acquired GAN induced by n-hexane can be differentiated from hereditary GAN by a late age at onset, a history of industrial or recreational exposure, a lack of kinky hair or CNS involvement, and improvement after removing the exposure as seen in our patient. Thorough history taking, especially the occupational and recreational history, is important to raise the suspicion. Nerve biopsy is diagnostic as seen in our case, which may otherwise be misdiagnosed with and wrongly managed for chronic inflammatory demyelinating polyneuropathy or other forms of polyneuropathy.

The clinical course of polyneuropathy induced by n-hexane exposure tends to be biphasic with “coasting” phenomenon (continued symptoms after removal of insulting agent, as seen in some chemotherapy-induced polyneuropathy) for 2–3 months, followed by a slow improvement or recovery in about 1–2 years after the cessation of the n-hexane exposure [1–3, 5, 15]. Prognosis is usually favorable, but some patients may have a protracted recovery course or permanent disability if initial axonal damage is severe.

N-hexane exposure at workplace needs to be investigated and recreational exposure needs to be considered in a patient with acquired GAN. Using safer solvents with adequate ventilation system in factories of shoe furniture, automotive, and printing industries is critical to prevent the disease. This case has profound implications for occupational health.

Pearls