xRead - Olfactory Disorders (September 2023)

20426984, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/alr.22929, Wiley Online Library on [04/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

383

PATEL et al.

Autoimmune diseases are a potential cause of OD. Aggregate grade of evidence : C (Level 2: one study; Level 4: 55 studies).

suggesting that RT-induced OD is both qualitative and quantitative. 384–390 Various mechanisms have been proposed regarding the pathophysiology of these observed changes, although there is limited evidence in their validation. Proposed mech anisms include direct cytotoxic damage to the OE, OB, or its supporting cells; impaired neurogenesis; treatment induced obstruction of the OC; and decreased vascular perfusion to the OC. Murine models have demonstrated that ionizing radiation affects olfactory neurogenesis and OB plasticity. 391,392 Patients with nasopharyngeal cancer treated with RT have been shown to exhibit reductions in OBV on posttreatment MRI, measured ≥ 1 year after com pletion of therapy. 390 Regarding prognosis, there appears to be a radiation dose-dependent effect on long-term OD. 384,385,393 However, individual outcomes may be unpredictable, as Jilali et al 393 demonstrated that the actual dose delivered to the nasal mucosa and OC is variable despite similar total radiation doses. This finding may explain some of the inconsistency in published outcomes of olfaction following RT. Radiation to the olfactory system can lead to OD that is sometimes temporary but can be permanent in some patients. Aggregate grade of evidence : C (Level 2: one study; Level 3: seven studies; Level 4: two studies). G Related to underlying systemic disease 1 Autoimmune Our systematic literature review identified that olfactory impairment is observed in many autoimmune diseases that have different underlying pathophysiology (Table VII.9). We identified studies in primary Sjögren syndrome, 394–401 systemic sclerosis, 402,403 multiple sclerosis, 404–431 gran ulomatosis with polyangiitis, 432–436 systemic lupus erythematosus (SLE), 403,437–439 rheumatoid arthritis, 440 myasthenia gravis, 441–443 neuromyelitis optica, 444 Behçet disease, 445–447 and Mikulicz disease. 448 Studies have used different methodologies but associations with age, sex, 398,409,415,421 and mood disorders 397,402,403,408,409 have been observed. Association with disease activity, 395,403,405,409,410,412,413,415–418,420,421,425–428,430,435,436 438,439,441,442 neurological manifestations, 403,405–411,413,415,418 420,421,425–428,430,431,437 magnetic resonance imaging (MRI) abnormalities, 403,406,411,414,418,419,423,429,444,447 and autoantibodies 403,441,444,445 have been found in different autoimmune diseases. There are only four longitudinal studies, and therefore results regarding worsening or stabilization of OD are controversial. 403,425,428,430

2 Vitamin-mineral deficiency Vitamins and minerals play a crucial role in healthy main tenance of the olfactory mucosa, neuronal pathway, and repair mechanisms, and disorders involving them can therefore derange the system. Zinc is widely known to be a trace metal involved in the enzyme activity of cell proliferation. 449 As a result, it has been considered an important element when main taining OF. Deficiency in this trace metal has been linked with anosmia, but excess has also been associated with toxic effects on the olfactory system. 449,450 Mechanisms for the latter include inhibition of glutathione reduc tase, induction of necrosis, impairment of the electron transport chain, and dysregulation of copper or calcium homeostasis. 450–452 Furthermore, deficiencies in copper and nickel can produce similar smell alterations when assessing receptor response profiles. 449 The OR neurons primarily use glutamate, a neurotrans mitter, during the excitation phase. Concentration varia tions can cause oxidative stress, as shown in AD, and can occur secondarily to low vitamin E levels. These alterations in concentrations can ultimately lead to shifts in smell sensation. 453–455 The mechanism for regeneration of the OE is not entirely clear, although specific pathways have been noted. Of these, vitamin A and its metabolites play an important role in tissue development and regeneration, with deficien cies implicated during olfactory embryogenesis and adult regeneration. 449,456,457 B vitamins, including vitamin B6 and B12, play a crucial role in growth and development, specifically in nerve perseveration of the smell sensation. Vitamin B12 can affect nerve function in multiple locations, includ ing the spinal cord, brain, optic nerve, and peripheral nerves. With regards to olfaction, the mechanism of action is similar and can produce clinically symptomatic patients through deficiencies, although no difference in treatment. 449,458 As shown through the importance of multiple vita mins and minerals, ultimately malnutrition can have a significant negative effect on the olfactory organ. This can occur through protein and calorie deficits, total parenteral nutrition without adequate replacement, spe cific vitamin or mineral insufficiency, or other dietary deficiencies. Although it would be mechanistically rea sonable to consider vitamin and mineral deficiencies to cause OD, there is no high-level data to currently prove this.