Myalgic Encephalomyelitis (ME) or What? An Operational Definition

Myalgic encephalomyelitis (ME), identified as a new clinical entity with distinctive features in 1956, was originally considered as a neuromuscular disease. In 1988 the Centers for Disease Control and Prevention introduced the ill-defined concept of chronic fatigue syndrome (CFS). As predicted, CFS, unjustly considered to be a synonym for ME, pushed ME to the background. To develop effective therapies for of ME and CFS, it is essential to investigate patients with ME specifically. For that reason, an operational definition of ME is indispensable. This article proposes an operational definition based on the most recent formal definitions and symptoms observed in ME. ME is a multi-systemic illness, which (1) often has a sudden onset, in most cases a respiratory and/or gastro-intestinal infection, but a gradual or more dramatic onset is also possible; (2) has an epidemic and an endemic form; (3) has an unique clinical pattern deviating from other post-viral states; (4) is distinguished by muscle fatigability/prolonged muscle weakness after trivial exertion; (5) is accompanied by symptoms relating to neurological disturbance, especially of cognitive, autonomic, and sensory functions; (6) can be accompanied by symptoms associated with cardiac and other systems; (7) is characterized by fluctuation of symptoms (within and between “episodes”); (8) has a prolonged relapsing course; and (9) has a tendency to become chronic. In conclusion, a discriminative definition for ME contains four mandatory elements: (1) muscle fatigability/post-exertional muscle weakness lasting for days; (2) operational criteria for “neurological disturbance, especially of cognitive, autonomic and sensory functions”; (3) fluctuation of symptoms; and (4) a prolonged relapsing course. This tentative definition of ME justifies the qualification “neuromuscular disease”.

In 1988 the US Centers for Disease Control and Prevention (CDC) introduced the ill-defined notion of chronic fatigue syndrome (CFS) [10]. CFS was redefined in 1994 [11]. The only mandatory feature of CFS [11] is (unexplained) chronic fatigue. Chronic fatigue must be accompanied by at least four out of a list of eight "minor" symptoms: sore throat; tender cervical or axillary lymph nodes; muscle pain, multi-joint pain without joint swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 h [11]. The case Table 1. The most recent formal definitions of ME (1990) [3].

Definition of ME (1990)
"A syndrome commonly initiated by respiratory and/or gastro-intestinal infection but an insidious or more dramatic onset following neurological, cardiac or endocrine disability occurs. The pathognomonic features (of ME) are: 1.
Complaint of general or local muscular fatigue following minimal exertion with prolonged recovery time.
Variable involvement of cardiac and other systems.

4.
A prolonged relapsing course. Other characteristics include [..] a prolonged relapsing course and variation in intensity of symptoms within and between episodes, tending to chronicity." Table 2. The most recent formal definitions of ME (1992) [4].

Definition of ME (1992)
"A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal illness but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised. The cardinal features, in a patient who has previously been physically and mentally fit, with a good work record are: 1.
Generalised or localised muscle fatigue after minimal exertion with prolonged recovery time.

2.
Neurological disturbance, especially of cognitive, autonomic and sensory functions, often accompanied by marked emotional lability and sleep reversal. 3.
Variable involvement of cardiac and other bodily systems.

4.
An extended relapsing course with a tendency to chronicity. 5.
Marked variability of symptoms both within and between episodes." Diagnostics 2018, 8, x 3 of 11 Table 2. The most recent formal definitions of ME (1992) [4].
Definition of ME (1992) "A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal illness but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised.
The cardinal features, in a patient who has previously been physically and mentally fit, with a good work record are: 1.
Generalised or localised muscle fatigue after minimal exertion with prolonged recovery time.

2.
Neurological disturbance, especially of cognitive, autonomic and sensory functions, often accompanied by marked emotional lability and sleep reversal. 3.
Variable involvement of cardiac and other bodily systems.

4.
An extended relapsing course with a tendency to chronicity. 5.
Marked variability of symptoms both within and between episodes."  The symptoms mentioned in epidemic and endemic cases of ME [1] were analysed and classified (Steps 3 and 5). The symptoms and symptom categories were checked against symptoms observed in 420 patients with well-defined ME [3] (Step 4). In Step 2a it was learnt that in addition to muscle fatigability/prolonged muscle weakness after exertion, "neurological disturbance, especially of cognitive, autonomic and sensory functions" is a mandatory symptomatic feature in the definition of ME.
To define operational criteria, the 50 neurological symptoms mentioned in cases of ME [1,3] were divided into five categories (Step 6): cognitive dysfunction, autonomic dysfunction, sensory dysfunction, motor dysfunction, and unclassified symptoms.
The basic assumption was that a patient should experience at least one symptom related to cognitive dysfunction, at least one symptom related to autonomic dysfunction, and at least one symptom associated with sensory dysfunction in order to meet the operational criteria of ME. However, considering the frequency of the symptoms reported by 420 patients with ME [1,3] and the number of times specific symptoms were mentioned in the description of cases of ME [16], two changes were made (Step 7a). First, since only three symptoms observed [1,3] relate to cognitive disturbance, and not all patients experience these three symptoms [3], it was decided that "cognitive dysfunction" symptoms should be combined with three other symptoms often reported by patients with ME [3] (two unclassified neurological symptoms related to sleep and headaches) in order to meet the first operational criterion for "neurological disturbance". Second, because symptoms related to sensory dysfunction are diverse and this category contains various symptoms often experienced by patients [1,3], it was decided that a patient should report at least two symptoms of the "sensory symptoms" subcategory to meet the minimal requirement for "sensory dysfunction".

Characteristics
3.1.1. An Epidemic and an Endemic Form ME has been described in the medical literature since 1936 [6]. This was often on account of outbreaks [5,17], the two most well-known being the epidemic in Akureyri district in Iceland (1948)(1949) [18] and the outbreak in the Royal Free Hospital (London, UK) in 1955 [15]. However in the 1950s it became evident that ME can also occur in sporadic form [5,16]: "Endemic prevalence alternates with periodic epidemics, showing a curious predilection for female staff of health care and teaching institutions" [3].
3.1.2. An Often Sudden, Sometimes Gradual, Onset ME often has a sudden onset; in most cases an infection described as a respiratory and/or gastro-intestinal illness, "but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised." [4]. This implies that a sudden onset is not a distinctive feature of ME as suggested by others [19][20][21].

An Acute and a Chronic Phase
"The onset [..] is usually acute with systemic prodromata such as are common in poliomyelitis." [7]. In the outbreaks, the prodromal phase was usually followed by improvement for a few hours, days or weeks, after which the symptoms returned more severely with additional symptoms, including marked muscle weakness [1,22].
In many cases the symptoms become chronic with a periodic relapsing course [1].

Not Just Like Other Post-Viral Fatigue States
ME should be distinguished from other forms of "post-viral debility following Epstein-Barr mononucleosis, influenza and other common fevers" [3] since ME has "an unique clinical and epidemiological pattern" [3] and these other post-viral states "lack the dramatic effect of exercise upon muscle function, the multisystem involvement, diurnal variability of symptoms and prolonged relapsing course" [3]. This is also one of the many reasons why ME [1][2][3][4] should not be confused with CFS [11], an ill-defined syndrome which can be initiated by various infections, e.g., the Epstein-Barr virus (mononucleosis), Coxiella burnetii (Q fever), or Ross River virus infections [23].

A Prolonged Relapsing Course
A distinctive feature of ME is a prolonged relapsing course. Years can pass between two relapses. Relapses can be caused by physical and mental stress (very often) and intercurrent infection (often). Although outbreak patients appear to recover much often than sporadic patients [22], the illness often lasts for years or even decades.

Diurnal Variability of Symptoms
In addition to periodic relapses or partial remission, ME is characterized by a strong fluctuation of symptoms during the course of the day and over time [1,3]. Physical and/or mental stress can have a (prolonged) negative effect on the symptoms [1].

Symptoms
Although ME is a multi-systemic disease [3] with a large range of symptoms that can vary greatly per patient per day, the distinctive features of ME are limited to muscle fatigability/post-exertional muscle weakness, and specific neurological symptoms.
Patients often report various other symptoms relating to the muscles and "variable involvement of cardiac and other bodily systems" [3], e.g., myalgia (80%), and gastro-intestinal symptoms (49%), but these symptoms are not noted in all cases of ME.
3.2.1. Muscle Fatigability/Prolonged Muscle Weakness after Exertion is a Mandatory Feature of ME "ME is [..] distinguished by severe muscle fatigue following trivial exertion" [3]. "Muscle fatigability is the dominant and most persistent feature of the disease and [..] a diagnosis should not be made without it. Restoration of muscle power after exertion can take three to five days or even longer." [1]. This implies that muscle fatigability/prolonged muscle weakness after exertion is a discriminative feature of ME. Long-lasting muscle weakness after exertion can be validated objectively by measuring muscle power of the arms, hands [24,25], legs [26,27], etc., during repeated muscle contractions on two consecutive days using dynamometers [28,29].

Neurological Disturbance Is an Essential Feature of ME
In addition to muscle fatigability/post-exertional muscle weakness, neurological symptoms are distinctive for ME. Neurological disturbance in ME especially relates to "cognitive, autonomic and sensory functions" [1]. Many symptoms observed in epidemic and endemic cases of ME [1] are related to neurological dysfunction. The neurological symptoms relate to cognitive dysfunction (n = 3), autonomic dysfunction (n = 11), sensory dysfunction (n = 19), and motor dysfunction (n = 4), while three symptoms (headache and symptoms related to sleep) are unclassified (Table 3). Considering the most recent definitions of ME [3,4] and the frequency of symptoms reported by 420 patients [3], a patient should experience at least one symptom related to cognitive dysfunction (n = 3) or one unclassified neurological symptom (n = 3), one symptom related to autonomic dysfunction (n = 11) and two symptoms related to sensory dysfunction (n = 19) to meet the proposed operational definition of ME [1][2][3][4]. Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.

Motor Dysfunction
Complete paralysis; Paralysis of the limbs (arms and legs) Paralysis of the face; Paralysis of swallowing; Poor movement of the soft palate; Mental confusion.

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli);  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli);  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.

Motor Dysfunction
Complete paralysis; Paralysis of the limbs (arms and legs) Paralysis of the face; Paralysis of swallowing; Poor movement of the soft palate; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.

Motor Dysfunction
Complete paralysis; Paralysis of the limbs (arms and legs) Paralysis of the face; Paralysis of swallowing; Poor movement of the soft palate; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.;  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.

Motor Dysfunction
Complete paralysis; Paralysis of the limbs (arms and legs) Paralysis of the face; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.;  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.

Motor Dysfunction
Complete paralysis; Paralysis of the limbs (arms and legs) Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.;  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.

Motor Dysfunction
Intolerance of extremes of temperature/hypersensitivity to climatic change; Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.

Motor Dysfunction
Abnormal dryness of the skin of the extremities (head, arms and feet);  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise); Tinnitus; and Deafness.
Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hyperacusis (intolerance of loud noise);

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, "dancing eyes"); Hypertrichosis (abnormal amount of hair growth over the body).

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli);  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Muscle tenderness: below the ribs;  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Muscle tenderness: shoulder girdle, e.g., trapezii; Diminished or absent vibration sense of hands/fingers and feet/toes;  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hyperesthesia (excessive physical sensitivity, especially of the skin); Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hyperalgesia (increased sensitivity to painful stimuli); Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Muscle tenderness: shoulder girdle, e.g., trapezii; Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes; Diminished or absent vibration sense of hands/fingers and feet/toes;  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Diminished or absent position sense of hands/fingers and feet/toes;  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); Blurring of (near) vision; Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Diplopia (simultaneous perception of two images of a single object); Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Sensory Dysfunction
Paraesthesia (abnormal sensations such as tingling, tickling, pricking, "pins and needles", numbness, itching or burning of the skin with no apparent cause);

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth over the body).

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Brittle nails (onychorrhexis); and Deafness.

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and feet);  Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3].

Cognitive Dysfunction
Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Mental confusion.

Autonomic Dysfunction
Future surveys should make clear if stricter requirements can be imposed on the three neurological criteria, and if symptoms not mentioned in the original description of endemic and epidemic cases [1] can be added to these neurological symptoms clusters, without excluding patients meeting the minimal requirement for "neurological disturbance".
Forthcoming studies should also establish the frequency of the (optional) symptoms related to other bodily systems observed in endemic and epidemic cases of ME [1] and mentioned in other diagnostic criteria, e.g., the International Consensus Criteria for ME (ME-ICC) [30], the Fukuda criteria for CFS [11], and the criteria for Systemic Exertion Intolerance Disease (SEID) [13].
Prospective studies should also investigate the overlap and differences between patients meeting the four different systems for diagnoses: ME [1][2][3][4], ME-ICC [30], CFS [11], and SEID [13], and the relative numbers of patients fulfilling one or more of these diagnoses.
Future research should also clarify which signs are exhibited by all patients meeting the operational definition (the "minimum criteria") of ME and can be included in the definition, and which comorbidities (symptom patterns) are often present in ME.