Delayed neurotoxic complications of chemical warfare agents (CWA), such as sulphur mustard (SM), in human beings have not been investigated in detail, due to methodological limitations for confirmation and attribution of potential neurological complications years after the exposure to SM. Even some researches that have studied and reported SM-induced psychological disorders put that they did not observe neurological complications in chronic poisonings (Balali-Mood and Navaeian 1986). However, neurological manifestations such as cholinergic syndromes and CNS depression are prominent following nerve agent exposure (Balali-Mood 1992; Balali-Mood 2008). Nerve agents have a much higher mortality rate than blistering agents and SM. Animal studies have shown that severe exposure to SM could affect CNS and cause seizure in the animal (Anslow and Houk 1946). Yet, examining the effects of SM on CNS in human beings is associated with certain difficulties. For example, SM exposure dose cannot be measured exactly in combat environments, since this factor is influential in causing neurological complications. Although there are some definitions such as severe chronic complications including skin blisters for assessing severity, they are not always applicable in battle conditions as the exposure dose is not always measurable; especially, when the soldiers have to stay in the exposed area for a long time. There are several other factors affecting the severity of complications, such as temperature, humidity, wind direction, personal protective equipment, and activity level of the soldier (Balali-Mood and Hefazi 2006; Perrotta 1996). Since, all veterans of Iran-Iraq war were poisoned with SM via inhalation; influence of the other routes of entry (Newmark 2007; Lotti and Moretto 1999) on neurological system of the soldiers cannot be assessed.

Chronic effects of SM exposure have been investigated in several studies. However, a number of reports have mentioned different complications, the most important and prevalent neurological complications include: headache, fatigue, chronic neuropathy, paramnesia, impaired concentration, dizziness, tremor, and seizures.

The most common psychiatric disorder attributed to exposure to severe traumatic events such as war and combat is post-traumatic stress disorder (PTSD). It was first described during the civil war and was named “soldier’s heart”. Since then it has been described under various names such as irritable heart, effort syndrome, combat stress reaction, and Persian Gulf War syndrome (Sadock et al. 2014). It affects approximately 9 % of the general population and up to 30 % of individuals who have experienced combat. It seems to develop more frequently in women when exposed to comparable traumatic events (Sadock et al. 2014).

There are some risk factors predisposing an individual to PTSD such as: being female, neuroticism, past history of prior trauma (especially in childhood), past history of PTSD, depression, or anxiety disorders, comorbid Axis II disorders (especially borderline, paranoid, dependent, or antisocial personality disorder), family history of mood, anxiety, or substance abuse disorders, disrupted parental attachments, severity of exposure to trauma, lower social support, and lower intelligence quotient (IQ). High premorbid intelligence may be protective against PTSD (Hales et al. 2008; Sadock et al. 2014; McNally 2009).

The biological models proposed for PTSD include: limbic hyperactivity and cortical hypo-responsivity to traumatic stimuli, dysfunction of the hypothalamic-pituitary-adrenal axis, noradrenergic dysregulation, abnormality in endogenous the opioid system, sensitized serotonergic system, and reduced hippocampal volume (Hales et al. 2008; Sadock et al. 2014; McNally 2009; Ehlers 2003).

The clinical diagnostic features of PTSD are categorized in four domains according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The first domain is intrusive symptoms, which include recurrent, involuntary, and intrusive recollections, dreams, dissociative flashbacks, psychological distress, and physiological reactions related to the traumatic event. The second domain is avoidance of stimuli associated with the traumatic event, whether internal (memories, thoughts, or feelings) or external (people, places, conversations, activities, objects, situations). The third one is negative alterations in cognitions and mood. This includes Inability to remember an important aspect of the traumatic event, negative beliefs or expectations about oneself, others, or the world, or about the cause or consequences of the traumatic event, persistent negative emotional state, diminished interest in significant activities, feelings of detachment or estrangement from others, and a persistent inability to experience positive emotions. The last domain is marked alterations in arousal and reactivity, including irritable behavior and angry outbursts, reckless or self-destructive behavior, hypervigilance, exaggerated startle response, problems with concentration, and sleep disturbance (American Psychiatric Association 2013).

It can also be accompanied by dissociative symptoms such as derealization and depersonalization, auditory pseudo-hallucinations (such as hearing one’s thoughts spoken), as well as paranoid ideation (American Psychiatric Association 2013).

“Survivor guilt” (guilt about having survived or not having prevented the traumatic experience, or about what one had to do in order to survive) is another feature commonly seen in combat-related PTSD. Other probable accompanying symptoms include: depression, anxiety, panic attacks, feelings of rejection, humiliation, shame, and rage, and emotional numbness. Prolonged episodes of intense affect or explosive, hostile and impulsive behavior may also happen (Hales et al. 2008; Sadock et al. 2014; McNally 2009; Ehlers 2003).

Other conditions complicating PTSD may include substance abuse, self-injurious behavior and suicide attempts, and impaired occupational or interpersonal function (Hales et al. 2008).

PTSD has a varied range of clinical presentation. In some people re-experiencing, emotional and behavioral symptoms predominate. In others anhedonia, dysphoric mood and negative cognitions are the major source of distress. Still in others, symptoms of arousal or dissociative symptoms may be prominent (American Psychiatric Association 2013). Comorbidity of PTSD with depression and anxiety disorders (such as OCD, panic disorder and phobia) is rather the rule than the exception, and it is associated with higher impairment in functioning. PTSD can have a delayed expression, even years after the traumatic events, but may be overlooked or ignored.

The disorders, most commonly considered in the differential diagnosis of PTSD include: acute stress disorder, major depression, adjustment disorder, panic disorder, generalized anxiety, disorders with intrusive thoughts and perceptual disturbances (e.g. obsessive compulsive disorder, schizophrenia), agoraphobia, specific phobia, adjustment disorder, borderline personality disorder, dissociative disorders, factitious disorders, and malingering (Hales et al. 2008; Sadock et al. 2014; McNally 2009; Ehlers 2003).

The majority of patients develop PTSD symptoms immediately after the traumatic event. Delayed onset is found in 11 % of the cases. Of those with initial PTSD symptoms, about 50 % will recover during the first year. Almost one third of those with PTSD have a chronic course. In 80 % of the cases, PTSD lasts longer than 3 months, in 75 % longer than 6 months, and in 50 % for 2 years’ duration. The average time for PTSD remission is 36 months for those who seek help for any mental health problem (not necessarily for PTSD), and about 64 months for those who never seek help. A minority can remain symptomatic for years or decades. Predictors of worse outcome include: female sex, being very young or very old, greater number or severity of PTSD symptoms, slow onset of the symptoms, longer duration of the symptoms (more than 6 months), higher numbing or hyperarousal to stressors, history of childhood trauma, poor premorbid functioning, poor social supports, and comorbid psychiatric, medical, or substance-related disorders (Hales et al. 2008; Sadock et al. 2014; McNally 2009; Ehlers 2003).

Toxic exposure to sulfur mustard almost always happens in combat and war conditions and might significantly increase the likelihood of PTSD development in the exposed individuals up to 40–60 % (Falahati et al. 2010; Mohaghegh-Motlagh et al. 2012; Hashemian et al. 2006; Schnurr et al. 1996, 2000). It leads to reduced physical health, higher rates of chronic illness and disability (which is quite common in individuals exposed to sulfur mustard), greater functional impairment, and higher likelihood of health care supports (Schnurr et al. 2000).

Individuals exposed to both high-intensity warfare and chemical weapons have been shown to have higher rates of PTSD than those exposed to high-intensity warfare but not to chemical weapons (Hashemian et al. 2006).

Psychological reactions at the time of mustard gas exposure have a strong association with PTSD symptoms. Strong peritraumatic stress or dissociative reactions may lead to psychobiological changes which may persist for decades in some cases (Jankowski et al. 2004). Female gender, older age, non-volunteer status, lower preparation for combat, witnessing trauma in others (especially loved ones), prohibited disclosure of the experience, poor physical health, chronic illness and disability, healthcare usage, and functional impairment are the main predisposing factors for PTSD in individuals exposed to mustard gas (Schnurr et al. 2000; Jankowski et al. 2004). The number of exposures to sulfur mustard can also predict lifetime PTSD. Academic education in the individual or his/her spouse can be a protective factor against PTSD in individuals exposed to mustard gas (Karami et al. 2013).

Exposure to chemical gases is a major traumatic incident that can risk the patient’s mental health in short-term and long-term, and cause permanent psychological problems. Anyone who has been severely exposed to chemical agents, experiences feelings of helplessness, anxiety, and decreased perceived safety (Hashemian et al. 2006). The subsequent chronic physical complications pose more challenges to the patient, make him prone to psychological symptoms and disorders, and affect his quality of life. Apart from PTSD and neuropsychiatric impairments discussed above, depression, anxiety, sexual, and sleep disorders, as well as long-term impact of SM injuries on quality of life have been investigated in some studies. In the following sections, the symptoms, disorders, and therapeutic methods will be discussed in the summary.