diagnostics Hypothesis
Myalgic Encephalomyelitis (ME) or What? An Operational Definition Frank Twisk ME-de-Patiënten Foundation, Zonnedauw 15, 1906 HB Limmen, The Netherlands;
[email protected]; Tel.: +31-72-505-4775 Received: 3 August 2018; Accepted: 6 September 2018; Published: 8 September 2018
Abstract: 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”. Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; diagnosis; neuromuscular; neurological disorders
1. Introduction Myalgic encephalomyelitis (ME) [1–4], in the literature also referred to as epidemic neuromyasthenia [5] and non-paralytic [3] or “atypical” [6] poliomyelitis, is a neuromuscular disease which was identified as a distinct clinical entity for the first time in 1956 [7]. At that time it was evident that muscular symptoms (e.g., paresis and myalgia) and neurological dysfunction were the hallmark features of ME [7]. ME [1–4] has been classified as a neurological disease by the World Health Organization (WHO) since 1969 [8,9]. 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
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criteria for CFS [11] define a heterogeneous group of patients with chronic fatigue (accompanied by 163 different combinations of “minor” symptoms) [12,13]. ME [1–4] and CFS [11] are two completely different concepts [14]. Chronic fatigue has never been described as a distinctive feature of ME [1–4], while muscle fatigability/prolonged post-exertional muscle weakness and specific neurological symptoms, discriminative features of ME [1–4], are not required to meet the diagnosis for CFS [11]. Despite the fact that ME [1–4], a typical neuromuscular disease, and CFS [11], a fatigue syndrome, are two completely different clinical entities by definition [14], CFS [11] has pushed ME completely to the background over the last decades. Thus, the vast majority of studies into “ME/CFS” published since 1990 relate to patients fulfilling the case criteria for CFS [11]. The confusion with regard with diagnosis and abnormalities which has arisen as a result of the introduction of the diagnosis of CFS was forecasted in 1988 by the renowned ME expert Dr. Betty Dowsett, who stated “The introduction of ‘chronic fatigue syndrome’ to designate ME does nothing to indicate the unique epidemio-logical, geographical, clinical, and laboratory findings in ME and can only add to the confusion surrounding the diagnosis, therapy, and prognosis of the condition” [2]. Due to the replacement of ME [1–4] by CFS [11], one of the last important studies investigating ME patients dates back to 1990 [3], just prior to the death of Melvin Ramsay, the recognized authority in ME. Dr. Ramsay was a consultant physician in infectious diseases at the Royal Free Hospital in London (United Kingdom) during an outbreak of ME in 1955 [15]. From that date until his death Ramsay was closely involved in ME cases. To unravel the aetiology and pathophysiology and to develop effective therapies for ME [1–4], it is essential to study patients with ME as described in the medical literature. For that reason an operational definition of ME [1–4] is indispensable. The aim of this study was to compose an operational definition of ME based on the definition and description in the most recent relevant articles [3,4], the symptoms and signs observed in the various epidemics (1934–1983) and endemic cases of ME [1], and the symptoms often and less-often experienced by 420 patients with ME [3]. 2. Method The starting point of the search of an operational definition of ME are the last two formal descriptions of ME [3,4]. As can be seen from Tables 1 and 2, the definitions of ME in these two publications [3,4] are essentially the same. The elements were classified as symptomatic features or characteristic features of the disease (Figure 1, Step 1). Based on the text, elements were classified as mandatory or optional (Step 2). For example the phrase “a tendency to chronicity” [4] implies it does not apply to all patients: it is an optional feature. This also applies to “variable involvement of cardiac and other systems” [3]. 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. 2. Neurological disturbance, especially of cognitive, autonomic and sensory functions. 3. 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.”
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Table 2. The most recent formal definitions of ME (1992) [4]. Diagnostics 2018, 8, 64
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Definition of ME (1992) “A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal Table 2. dramatic The most recent definitions of ME (1992) [4]. or endocrine illness but a gradual or more onset formal following neurological, cardiac disability is recognised. Definition of ME (1992)
“A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal illness but a
The cardinal features, in a patient who has previously been physically and mentally fit, with a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised. good work record The cardinal features,are: in a patient who has previously been physically and mentally fit, with a good work 1. Generalised or localised muscle fatigue after minimal exertion with prolonged recovery record are: 1. time. Generalised or localised muscle fatigue after minimal exertion with prolonged recovery time. 2. Neurological disturbance, especially of cognitive, autonomic and sensory functions, accompanied 2. Neurological disturbance, especially of cognitive, autonomic and sensoryoften functions, often by marked emotional lability and sleep reversal. accompanied by marked emotional lability and sleep reversal. 3. Variable involvement of cardiac and other bodily systems. 3. Variable involvement of cardiac and other bodily systems. 4. An extended relapsing course with a tendency to chronicity. 4. An extended course a tendency to chronicity. 5. Marked variabilityrelapsing of symptoms bothwith within and between episodes.” 5. Marked variability of symptoms both within and between episodes.”
Figure 1. 1. Method. Method. Figure
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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”. 3. Results 3.1. 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 [19–21]. 3.1.3. 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].
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3.1.4. 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 [1–4] 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]. 3.1.5. 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. 3.1.6. 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]. 3.2. 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]. 3.2.2. 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 [1–4].
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Cognitive Dysfunction Table 3. ofof patients observed in endemic andand epidemic casescases [1,3].[1,3]. Table 3.Neurological Neurologicalsymptoms symptoms patients observed in endemic epidemic Table 3. Neurological symptoms(impaired of patientsmemory observedor in concentration, endemic and epidemic cases [1,3]. in Neurocognitive impairment impaired ability
Cognitive Dysfunction Diagnostics 2018, 8, x 6 of 11 Cognitive Dysfunction calculation, using wrong words, forgetfulness, etc.); Cognitive Dysfunction Diagnostics 2018, 8, x 6 of 11 Neurocognitive impairment (impaired memory or concentration, impaired ability in Clumsiness/fumble with simplememory manoeuvres; and Neurocognitive impairment (impaired or concentration, impaired ability in calculation, using wrong Diagnostics 2018, 8,3. x Neurological Table symptoms of patientsetc.); observedor in concentration, endemic and epidemic cases [1,3]. in 6 of 11 Neurocognitive (impaired memory impaired ability calculation, using wrongimpairment words, forgetfulness, words, forgetfulness, etc.); Mental confusion. Table 3. Neurological symptoms of patients observed calculation, using wrongwith words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; andin endemic and epidemic cases [1,3]. Clumsiness/fumble simple manoeuvres; and Cognitive Dysfunction Autonomic Dysfunction Diagnostics 2018, 8,3. x Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. 6 of 11 Table Clumsiness/fumble Mental confusion. Mental confusion. with simple manoeuvres; and Cognitive Dysfunction Neurocognitive impairment (when (impaired memory or concentration, impaired ability in Dizziness/giddiness/vertigo standing); Mental confusion. Autonomic Dysfunction Cognitive Dysfunction Autonomic Dysfunction Diagnostics 2018, 8,3. Table Neurological symptoms of patientsetc.); observedor in concentration, endemic and epidemic cases [1,3]. in 6 of 11 Neurocognitive (impaired memory impaired ability calculation, using wrongimpairment words, forgetfulness, Loss ofx equilibrium/imbalance/unsteadiness; Autonomic Dysfunction Diagnostics 2018, 8, x 6 of 11 Dizziness/giddiness/vertigo (when standing); Neurocognitive (impaired memory or concentration, impaired ability calculation, usingorthostatic wrongimpairment words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Dizziness/giddiness/vertigo (when standing); Postural tachycardia (POTS): an abnormal heart rate increase (≥30 beatsinper Cognitive Dysfunction Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Dizziness/giddiness/vertigo (when standing); Loss of confusion. equilibrium/imbalance/unsteadiness; calculation, using wrong words, forgetfulness, etc.);stilland Clumsiness/fumble with simple Loss Mental minute, oroftoequilibrium/imbalance/unsteadiness; beats per minute) aftermanoeuvres; standing for a while (can be delayed); Diagnostics 2018, 8,≥120 x Neurological 6 of 11 Table 3. symptoms(impaired of (POTS): patientsmemory observed in concentration, endemic and epidemic cases [1,3]. Neurocognitive impairment or impaired ability Loss of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia an abnormal rate (≥30 beatsinper Clumsiness/fumble with simple manoeuvres; and Postural orthostatic tachycardia (POTS): an abnormal heart rateheart increase (≥increase 30 beats minute, or to Mental confusion. Autonomic Dysfunction Cognitive Dysfunction Bladder dysfunction: disturbance of micturition (urination), difficulty in per starting Diagnostics 2018, 8, x 6 of 11 calculation, using wrong words, forgetfulness, etc.); ≥120 per minute) standing still for a while (can bea delayed); Postural orthostatic tachycardia (POTS): anstill abnormal heart(can rate be increase (≥30 beats per minute, orbeats toDysfunction ≥120 beats perafter minute) after standing forurinate), while delayed); Mental confusion. Autonomic Cognitive Dysfunction micturition, nocturia (wake at night one or more times to pollakiuria (often urinating Diagnostics 2018, 8, x Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Dizziness/giddiness/vertigo standing); Neurocognitive impairment (impaired memory or concentration, impaired abilitynocturia in 6 of 11 Clumsiness/fumble with simple manoeuvres; Bladder dysfunction: disturbance of(when micturition (urination), in starting micturition, minute, or toDysfunction ≥120 beats per minute) after standing stilland for adifficulty while (can be delayed); Bladder dysfunction: disturbance ofstanding); micturition (urination), difficulty incases starting Autonomic Table 3. Neurological symptoms of patients observed in endemic and epidemic [1,3]. small amounts), etc.; Dizziness/giddiness/vertigo (when Neurocognitive impairment (impaired memory or concentration, impaired ability Loss of equilibrium/imbalance/unsteadiness; calculation, wrong words, forgetfulness, etc.); (wake atusing night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; in Mental confusion. Cognitive Dysfunction Bladder dysfunction: disturbance ofmore micturition (urination), difficulty in starting micturition, nocturia (wake at night one or times to urinate), pollakiuria (often urinating Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Dizziness/giddiness/vertigo (when standing); Symptoms related towith impaired extremities (hands, feet, etc.), ashen-grey Loss of related equilibrium/imbalance/unsteadiness; calculation, using wrong words, forgetfulness, Postural orthostatic tachycardia (POTS): ancold abnormal heart rate increase (≥30facial beatspallor, per etc.; Clumsiness/fumble simplecirculation: manoeuvres; and Symptoms to impaired circulation: coldetc.); extremities (hands, feet, etc.), ashen-grey Autonomic Dysfunction Cognitive Dysfunction micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Diagnostics 2018, 8,ofx equilibrium/imbalance/unsteadiness; 6 of 11 small amounts), etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability in Loss facial pallor, Postural orthostatic tachycardia anstill abnormal heart(can ratefeelings increase beats per Clumsiness/fumble simple manoeuvres; and Symptoms related to thermoregulation: feeling cold, chills, of (≥30 feverishness minute, or Dysfunction toetc.; ≥120 beats per with minute) after(POTS): standing forhypothermia, a while be delayed); Mental confusion. Cognitive Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. small(with/without amounts), etc.; Dizziness/giddiness/vertigo (when standing); Neurocognitive impairment (impaired memory or concentration, impaired ability in Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey calculation, using wrong words, forgetfulness, etc.); fever), episodes of extreme sweating, etc.; Postural orthostatic anstill abnormal heart(can rate increase (≥30 beatsofper Symptoms related thermoregulation: feeling cold, chills, hypothermia, feelings minute, Bladder or toDysfunction ≥120 beats pertotachycardia minute) after(POTS): standing for a while be delayed); Mental confusion. dysfunction: disturbance of micturition (urination), difficulty in starting Autonomic Table 3. equilibrium/imbalance/unsteadiness; Neurological symptoms ofcirculation: patients observed inclimatic endemicchange; and epidemic [1,3]. Neurocognitive impairment (impaired memory or concentration, impaired ability in Symptoms related towith impaired cold extremities (hands, feet, cases etc.), ashen-grey Loss of calculation, using wrong words, forgetfulness, etc.); facial pallor, etc.; Clumsiness/fumble simple manoeuvres; and Intolerance of extremes of temperature/hypersensitivity to minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); feverishness (with/without fever), episodes of extreme sweating, etc.; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Autonomic Dysfunction Cognitive Dysfunction micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating6 of 11 Diagnostics 2018, 8, x Dizziness/giddiness/vertigo (when standing); calculation, using wrong words, forgetfulness, etc.); facial pallor, etc.; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per Clumsiness/fumble with simple manoeuvres; and Abnormal dryness of the skin of the extremities (head, arms and feet); Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Mental confusion. Bladder dysfunction: micturition (urination), difficulty in starting Cognitive Dysfunction Intolerance of(wake extremes of temperature/hypersensitivity to pollakiuria climatic change; micturition, nocturia atdisturbance night one orofmore times toor urinate), (often urinating smallExfoliation amounts), etc.; Dizziness/giddiness/vertigo (when standing); Neurocognitive impairment (impaired memory concentration, impaired ability in Loss of equilibrium/imbalance/unsteadiness; Clumsiness/fumble with simple manoeuvres; and of the skin of extremities (head, arms and feet), followed by atrophy of the skin and Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Mental confusion. feverishness (with/without fever), episodes of extreme etc.; Autonomic Dysfunction Diagnostics 2018, 8, x Neurological 6 of 11 micturition, nocturia (wake at night one or times sweating, to urinate), pollakiuria (often urinating Table 3. symptoms of patients observed in endemic and cases [1,3]. Abnormal dryness of the skin of themore extremities (head, arms andepidemic feet); smallsubcutaneous amounts), etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability Symptoms related to impaired circulation: extremities (hands, feet, etc.), ashen-grey Loss of equilibrium/imbalance/unsteadiness; calculation, using wrong words, forgetfulness, etc.); Postural orthostatic tachycardia (POTS): ancold abnormal heart rate increase (≥30 beatsinper tissue; Mental confusion. feverishness (with/without fever), episodes of extreme sweating, etc.; Bladder dysfunction: disturbance ofstanding); micturition (urination), difficulty in starting Autonomic Dysfunction Intolerance of extremes of temperature/hypersensitivity to climatic change; Diagnostics 2018, 8, x 6 of 11 Dizziness/giddiness/vertigo (when small amounts), etc.; Exfoliation of theper skin of extremities (head, arms and feet), followed by atrophy of the Symptoms related towith impaired circulation: extremities (hands, feet, etc.), calculation, using wrong words, forgetfulness, etc.); facial pallor, etc.; Postural orthostatic tachycardia (POTS): ancold abnormal heart(can rate be increase (≥30 ashen-grey beats per Clumsiness/fumble simple manoeuvres; and Brittle nails (onychorrhexis); and minute, or Dysfunction to ≥120 beats minute) after standing still for a while delayed); Cognitive Autonomic Dysfunction Intolerance of extremes of temperature/hypersensitivity to climatic change; micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Abnormal dryness of the skin of the extremities (head, arms and feet); Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Symptoms related towith impaired circulation: cold extremities (hands, feet, etc.), ashen-grey skin and subcutaneous tissue; facial pallor, Clumsiness/fumble simple manoeuvres; Hypertrichosis (abnormal amount of hair growth over the body). Symptoms related thermoregulation: feeling cold, chills, (can hypothermia, feelings of minute, or to8,etc.; ≥120 beats perto minute) after standing stilland for a while be delayed); Mental confusion. Bladder dysfunction: disturbance of micturition (urination), difficulty incases starting Diagnostics 2018, x equilibrium/imbalance/unsteadiness; Table 3. Neurological symptoms of patients observed in endemic and epidemic [1,3]. Abnormal dryness of the skin of the extremities (head, arms and feet); small amounts), etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability in Dizziness/giddiness/vertigo (when standing); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Loss of Postural orthostatic tachycardia an abnormal heart rate increase (≥30 beatsofper6 of 11 facial pallor, etc.; Brittle nails (onychorrhexis); and(POTS): Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings Mental confusion. feverishness (with/without fever), episodes of extreme sweating, etc.; Cognitive Dysfunction Bladder dysfunction: disturbance micturition (urination), difficulty in starting Autonomic Dysfunction micturition, nocturia (wake at night one orofmore times to urinate), pollakiuria (often urinating Sensory 2018, Dysfunction Diagnostics 8, x equilibrium/imbalance/unsteadiness; Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy ofof the Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey calculation, using wrong words, forgetfulness, etc.); Loss of skin and subcutaneous tissue; Postural orthostatic tachycardia an abnormal heart rate be increase (≥30 beats per6 of 11 minute, or Dysfunction toDysfunction ≥120 beats perto minute) after(POTS): standing still for a while (can delayed); Symptoms related thermoregulation: feeling cold, chills, hypothermia, feelings Hypertrichosis (abnormal amount of hair growth over the body). feverishness (with/without fever), episodes of extreme sweating, etc.; Cognitive Autonomic Intolerance of extremes of temperature/hypersensitivity to climatic change; micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Diagnostics 2018, 8, x 11 small amounts), etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Dizziness/giddiness/vertigo (when standing); skin and subcutaneous tissue; facial pallor, etc.; Clumsiness/fumble with simple manoeuvres; and Paraesthesia (abnormal such as tingling, tickling, “pins and needles”, numbness, Postural orthostatic tachycardia anstill abnormal heart rate increase (≥30 beats per6 ofitching Brittle nails (onychorrhexis); and(POTS): minute, or to(with/without ≥120 beats persensations minute) after standing for apricking, while (can be delayed); Bladder dysfunction: disturbance ofstanding); micturition (urination), difficulty incases starting feverishness fever), episodes of extreme sweating, etc.; Cognitive Dysfunction Intolerance of extremes of temperature/hypersensitivity to climatic change; Sensory Dysfunction Abnormal dryness of the skin of the extremities (head, arms and feet); Diagnostics 2018, 8, x 6 of 11 small amounts), etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic [1,3]. Dizziness/giddiness/vertigo (when Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey calculation, wrong words, forgetfulness, etc.); Loss of equilibrium/imbalance/unsteadiness; or burning of the skin with no apparent cause); Brittle nails (onychorrhexis); and Symptoms related toat thermoregulation: feeling cold, chills, hypothermia, feelings of Mental confusion. minute, or Dysfunction tousing ≥120 beats per minute) after standing stillto for a while (can befeet); delayed); Hypertrichosis (abnormal amount of hair growth over the body). Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Cognitive micturition, nocturia (wake night one or more times urinate), pollakiuria (often urinating Intolerance of extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the extremities (head, arms and Diagnostics 2018, 8, x 6 of Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey calculation, using wrong words, forgetfulness, etc.); Loss of equilibrium/imbalance/unsteadiness; facial pallor, etc.; Clumsiness/fumble with manoeuvres; and Hypoesthesia (reduced sense ofsimple touch or physical sensation/local numbness); Postural orthostatic tachycardia (POTS): an abnormal rate increase (≥30 beats per 11 Hypertrichosis (abnormal amount of hair growth overheart the body). feverishness (with/without fever), episodes of extreme sweating, etc.; Autonomic Dysfunction Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Cognitive Dysfunction Sensory Dysfunction micturition, nocturia (wake at night one or more times to(head, urinate), pollakiuria (often urinating small amounts), etc.; Abnormal dryness of the skin of the extremities arms and feet); Diagnostics 2018, 8, x Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy ofof the calculation, using wrong words, forgetfulness, etc.); skin and subcutaneous tissue; needles”, numbness, itching or burning of the stimuli); skin no aapparent cause); facial pallor, etc.; Clumsiness/fumble with simple manoeuvres; and Hypoalgesia (decreased sensitivity to painful Postural orthostatic tachycardia (POTS): anwith abnormal heart rate increase (≥30 beats per6 of 11 Symptoms related thermoregulation: feeling cold, chills, hypothermia, feelings Mental confusion. minute, or tonocturia ≥120 beats perto minute) after standing still for while (can be delayed); Intolerance of extremes of temperature/hypersensitivity to climatic change; Cognitive Dysfunction Sensory Dysfunction micturition, (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8,3. x Neurological Neurocognitive impairment (impaired memory or concentration, impaired ability in Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Table symptoms of patients observed in endemic and epidemic cases [1,3]. Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the calculation, using wrong words, forgetfulness, etc.); skin and subcutaneous tissue; Clumsiness/fumble with simple manoeuvres; and Diminished or absent position sense of hands/fingers and feet/toes; Brittle nails (onychorrhexis); and Hypoesthesia (reduced sense of touch orfeeling physical sensation/local numbness); Symptoms related thermoregulation: cold, chills, hypothermia, feelings of 6 of 11 Mental confusion. minute, or Dysfunction toDysfunction ≥120 beats perto minute) after standing stillsweating, for a while (can befeet); delayed); feverishness (with/without fever), episodes extreme etc.; Autonomic Bladder dysfunction: disturbance ofof micturition (urination), difficulty in starting Cognitive Abnormal dryness of the skin of the extremities (head, arms and small amounts), etc.; Diagnostics 2018, 8,etc.; x equilibrium/imbalance/unsteadiness; Neurocognitive impairment (impaired memory or concentration, impaired ability in 6 of 11 Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Loss of calculation, using wrong words, forgetfulness, etc.); needles”, numbness, itching or burning of the skin with no apparent cause); facial pallor, skin and subcutaneous tissue; Clumsiness/fumble with simple manoeuvres; and Diminished or absent vibration sense of hands/fingers and feet/toes; Brittle nails (onychorrhexis); and Mental confusion. Hypertrichosis (abnormal amount of hair growth over the body). Hypoalgesia (decreased sensitivity to painful stimuli); feverishness (with/without fever), episodes of extreme sweating, etc.; Autonomic Dysfunction Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Intolerance of extremes of temperature/hypersensitivity to climatic change; micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Cognitive Dysfunction Dizziness/giddiness/vertigo (when standing); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Diagnostics 2018, 8, x Neurocognitive impairment (impaired memory or concentration, impaired ability in Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Table 3.nails Neurological symptoms of of patients observed inthe endemic and epidemic cases [1,3]. calculation, using wrong words, forgetfulness, etc.); needles”, numbness, itching or burning the skin with no apparent cause); facial pallor, etc.; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsof per6 of 11 Clumsiness/fumble manoeuvres; and Hyperesthesia (excessive physical sensitivity, especially of skin); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Symptoms related towith thermoregulation: feeling cold, chills, hypothermia, feelings Brittle (onychorrhexis); and Mental confusion. Hypertrichosis (abnormal amount of hair growth over the body). Autonomic Dysfunction Sensory Dysfunction Diminished or absent position sense of hands/fingers and Intolerance of extremes ofsimple temperature/hypersensitivity tofeet/toes; climatic change; micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Cognitive Dysfunction Abnormal dryness of the skin of the extremities (head, arms and feet); small amounts), etc.; Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; Diagnostics 2018, 8, x Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. skin and subcutaneous tissue; calculation, wrong words, forgetfulness, etc.); facial pallor, etc.; Clumsiness/fumble with simple manoeuvres; and Hyperalgesia (increased sensitivity to stimuli); Hypoesthesia (reduced sense ofpainful touch or physical sensation/local Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of 6 of 11 minute, or tousing ≥120 beats per minute) after standing still for a while (can benumbness); delayed); Mental confusion. Hypoalgesia (decreased sensitivity to painful stimuli); feverishness (with/without fever), episodes of extreme sweating, etc.; Hypertrichosis (abnormal amount of hair growth over the body). Autonomic Dysfunction Sensory Dysfunction Cognitive Dysfunction Diminished or absent vibration sense of hands/fingers and feet/toes; Abnormal dryness of the skin of the extremities (head, arms andepidemic feet); small amounts), etc.; Dizziness/giddiness/vertigo (when standing); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy ofof the Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Loss of equilibrium/imbalance/unsteadiness; Diagnostics 2018, 8, x Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and cases [1,3]. Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per6 of 11 calculation, using wrong words, forgetfulness, etc.); Brittle nails (onychorrhexis); and Clumsiness/fumble with simple manoeuvres; and Muscle tenderness: upper and lower limbs (arms and legs, e.g.,chills, gastrocnemii); Symptoms related to thermoregulation: feeling cold, hypothermia, feelings Mental confusion. Hypoalgesia (decreased sensitivity to stimuli); feverishness (with/without fever), episodes of extreme sweating, etc.; Bladder dysfunction: disturbance ofstanding); micturition (urination), difficulty in starting Diminished or absent position sense ofpainful hands/fingers and feet/toes; Intolerance of extremes of temperature/hypersensitivity to climatic change; Autonomic Dysfunction Sensory Dysfunction Cognitive Dysfunction Dizziness/giddiness/vertigo (when Hyperesthesia (excessive physical sensitivity, especially of the skin); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Loss of equilibrium/imbalance/unsteadiness; Diagnostics 2018, 8, x Neurocognitive impairment (impaired memory or concentration, impaired ability in needles”, numbness, itching or burning of the skin with no apparent cause); skin and subcutaneous tissue; Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. facial pallor, etc.; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per6 of 11 calculation, using wrong words, forgetfulness, etc.); minute, or totenderness: ≥120 beats perfever), minute) after standing stilland forurinate), a while (can be delayed); Clumsiness/fumble with simple manoeuvres; Muscle shoulder girdle, e.g., trapezii; Hypertrichosis (abnormal amount of hair growth over the body). Mental confusion. feverishness (with/without episodes of extreme sweating, etc.; Diminished or absent position sense of hands/fingers and feet/toes; Intolerance of extremes of temperature/hypersensitivity to climatic change; Autonomic Dysfunction micturition, nocturia (wake at night one or more times to pollakiuria (oftenand urinating6 of 11 vibration sense of hands/fingers and feet/toes; Abnormal dryness of the skin of the extremities (head, arms and feet); Cognitive Dysfunction Dizziness/giddiness/vertigo (when standing); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins Loss of equilibrium/imbalance/unsteadiness; Diagnostics 2018, 8,etc.; xnails Neurocognitive impairment (impaired memory or concentration, impaired ability in Hyperalgesia (increased sensitivity to painful stimuli); needles”, numbness, itching or burning of the skin with no apparent cause); skin and subcutaneous tissue; Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. facial pallor, Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats calculation, using wrong words, forgetfulness, etc.); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Brittle (onychorrhexis); and Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Clumsiness/fumble with simple manoeuvres; and Muscle tenderness: below the ribs; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting per Mental confusion. Sensory Dysfunction Intolerance of extremes ofextremities temperature/hypersensitivity to climatic change; Autonomic Dysfunction Diminished or absent vibration of hands/fingers and feet/toes; Abnormal dryness oftachycardia the skin ofsense the extremities (head, arms and feet); small amounts), etc.; Cognitive Dysfunction Hyperesthesia (excessive physical sensitivity, especially of the skin); Exfoliation of the skin ofburning (head, arms and feet), followed by atrophy ofof the Dizziness/giddiness/vertigo (when standing); Loss equilibrium/imbalance/unsteadiness; Diagnostics 2018, 8,of xnails Neurocognitive impairment (impaired memory or concentration, impaired ability in needles”, numbness, itching or of the skin with no apparent cause); Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Postural orthostatic (POTS): an abnormal heart rate increase (≥30 beats per6 of 11 calculation, using wrong words, forgetfulness, etc.); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Brittle (onychorrhexis); and Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Clumsiness/fumble with simple manoeuvres; and Muscle tenderness: abdomen, e.g., abdominal recti; Hypoalgesia (decreased sensitivity to painful stimuli); Hypertrichosis (abnormal amount of hair growth over the body). feverishness (with/without fever), episodes of extreme sweating, etc.; Bladder dysfunction: disturbance ofmore micturition (urination), difficulty in starting Mental confusion. micturition, nocturia (wake atimpaired night one or times to urinate), pollakiuria (often urinating Autonomic Dysfunction Abnormal dryness of the skin of the extremities (head, arms and feet); Cognitive Dysfunction Hyperesthesia (excessive physical sensitivity, especially of the skin); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Symptoms related to circulation: cold extremities (hands, feet, etc.), ashen-grey Dizziness/giddiness/vertigo (when standing); Hyperalgesia (increased sensitivity to painful stimuli); skin and subcutaneous tissue; Loss of equilibrium/imbalance/unsteadiness; Diagnostics 2018, 8, x Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per6 of 11 calculation, using wrong words, forgetfulness, etc.); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Clumsiness/fumble with simple manoeuvres; and Blurring of (near) vision; Muscle tenderness: shoulder girdle, e.g., trapezii; Hypoalgesia (decreased sensitivity to painful stimuli); Hypertrichosis (abnormal amount of hair growth over the body). feverishness (with/without fever), episodes of extreme sweating, etc.; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Mental confusion. Diminished or absent sense of hands/fingers and Sensory Dysfunction Intolerance of extremes ofextremities temperature/hypersensitivity tofeet/toes; climatic change; micturition, nocturia (wake at position night one or more times to and urinate), pollakiuria (often urinating Autonomic Dysfunction small amounts), etc.;of Cognitive Dysfunction Exfoliation the skin of (head, arms feet), followed by atrophy of the Dizziness/giddiness/vertigo (when standing); Hyperalgesia (increased sensitivity to painful stimuli); needles”, numbness, itching or burning of the skin with no apparent cause); skin and subcutaneous tissue; facial pallor, etc.; Loss of equilibrium/imbalance/unsteadiness; Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Brittle nails (onychorrhexis); and Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per calculation, wrong words, forgetfulness, etc.); minute, or tousing ≥120 beats per minute) after standing for aobject); while (can delayed); Clumsiness/fumble with simple manoeuvres; and Diplopia (simultaneous perception ofribs; two images ofstill a stimuli); single Hypoalgesia (decreased sensitivity tomicturition painful Bladder dysfunction: disturbance ofsuch (urination), difficulty in starting Mental confusion. Muscle tenderness: below the Diminished or absent position sense ofof hands/fingers and Sensory Dysfunction Intolerance of extremes of temperature/hypersensitivity tofeet/toes; climatic change; micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating vibration sense hands/fingers and feet/toes; Autonomic Dysfunction Abnormal dryness of the skin of the extremities (head, arms andbefeet); small amounts), etc.; Paraesthesia (abnormal sensations as tingling, tickling, pricking, “pins and Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Cognitive Dysfunction Dizziness/giddiness/vertigo (when standing); skin and subcutaneous tissue; Loss of equilibrium/imbalance/unsteadiness; Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Brittle nails (onychorrhexis); and Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per calculation, using wrong words, forgetfulness, etc.); shoulder girdle, e.g., trapezii; Hypertrichosis (abnormal amount of hair growth over the body). minute, oroftoaccommodation ≥120 beats per(depth minute) after standing stilland for a while (can befeet); delayed); Clumsiness/fumble with simple manoeuvres; Loss perception); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Mental confusion. Diminished or absent position sense of hands/fingers and micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Muscle tenderness: abdomen, e.g., abdominal recti; vibration sense of hands/fingers and feet/toes; Autonomic Dysfunction Abnormal dryness of the skin of the extremities (head, arms and small amounts), etc.; Hyperesthesia (excessive physical sensitivity, especially offeet/toes; the skin); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and Exfoliation of the skin ofburning extremities (head, arms and feet), followed by“pins atrophy of in the Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Cognitive Dysfunction Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8,etc.; xnails needles”, numbness, itching or of the skin with no apparent cause); facial pallor, Loss of equilibrium/imbalance/unsteadiness; Neurocognitive impairment (impaired memory or concentration, impaired ability Brittle (onychorrhexis); and Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per6 of 11 calculation, using wrong words, forgetfulness, etc.); Muscle tenderness: shoulder girdle, e.g., trapezii; Hypoalgesia (decreased sensitivity to painful stimuli); Hypertrichosis (abnormal amount of hair growth over the body). feverishness (with/without fever), episodes of extreme sweating, etc.; minute, or toDysfunction ≥120 beats per minute) after stilland for a while (can be delayed); Clumsiness/fumble with simple manoeuvres; Photophobia/defective response toone light (sluggish pupils)/light hypersensitivity; below the ribs; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Sensory Dysfunction Mental confusion. micturition, nocturia (wake at night orstanding more times to urinate), pollakiuria (often urinating Diminished or absent vibration sense of hands/fingers and feet/toes; Autonomic small amounts), etc.; Blurring of (near) vision; Hyperesthesia (excessive physical sensitivity, especially of the skin); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Cognitive Dysfunction Hyperalgesia (increased sensitivity to painful stimuli); Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, x needles”, numbness, itching or burning of the skin with no apparent cause); skin and subcutaneous tissue; facial pallor, etc.; Loss of equilibrium/imbalance/unsteadiness; Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Symptoms related tobelow thermoregulation: feeling cold, chills, hypothermia, feelings Neurocognitive impairment (impaired memory or concentration, impaired ability inper6 of 11 Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsof calculation, wrong words, forgetfulness, etc.); Hypertrichosis (abnormal amount of hair growth over the body). minute, or tousing ≥120 beats per minute) after still for a while (can be delayed); Clumsiness/fumble with simple manoeuvres; and Nystagmus (involuntary eye movements, “dancing eyes”); Muscle tenderness: the ribs; Diminished or absent position sense of hands/fingers and Intolerance of extremes of temperature/hypersensitivity tofeet/toes; climatic change; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Sensory Dysfunction Mental confusion. abdomen, e.g., abdominal recti; micturition, nocturia (wake at night one orstanding more times to urinate), pollakiuria (often urinating Autonomic Dysfunction small amounts), etc.; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Hyperesthesia (excessive physical sensitivity, especially of the skin); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Diplopia (simultaneous perception of two images of a single object); Hyperalgesia (increased sensitivity to painful stimuli); Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, x skin and subcutaneous tissue; facial pallor, etc.; Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Loss of equilibrium/imbalance/unsteadiness; Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Brittle nails (onychorrhexis); and Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings Neurocognitive impairment (impaired memory or concentration, impaired ability inper6 of 11 Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsof Hypoalgesia (decreased sensitivity to painful stimuli); feverishness (with/without fever), episodes of extreme sweating, etc.; calculation, wrong words, forgetfulness, etc.); minute, or tousing ≥120 per minute) after standing still for a while (can be delayed); Clumsiness/fumble with simple manoeuvres; and Hyperacusis (intolerance of loud noise); Bladder dysfunction: disturbance ofabdominal micturition (urination), difficulty in starting Sensory Dysfunction Mental confusion. Muscle tenderness: abdomen, e.g., recti; Diminished or absent vibration sense of hands/fingers and feet/toes; Abnormal dryness of the skin of the extremities (head, arms and feet); micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Autonomic Dysfunction Blurring ofbeats (near) vision; small amounts), etc.; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey needles”, numbness, itching or burning of the skin with no apparent cause); Hyperalgesia (increased sensitivity to painful stimuli); Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, x facial pallor, etc.; Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. accommodation (depth perception); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Loss of equilibrium/imbalance/unsteadiness; Brittle nails (onychorrhexis); and Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of shoulder girdle, e.g., trapezii; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30urinating beats per6 of 11 Hypoalgesia (decreased sensitivity to painful stimuli); Hypertrichosis (abnormal amount of hair growth over the body). feverishness (with/without fever), episodes of extreme sweating, etc.; calculation, wrong words, forgetfulness, etc.); minute, or Dysfunction tousing ≥120 beats per minute) after still for a while (can be delayed); Diminished or absent position sense of hands/fingers and feet/toes; Intolerance of extremes of temperature/hypersensitivity to climatic change; Clumsiness/fumble with simple manoeuvres; and Tinnitus; and Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Mental confusion. micturition, nocturia (wake at night one orstanding more times to urinate), pollakiuria (often Autonomic Dysfunction Blurring of (near) vision; Hyperesthesia (excessive physical sensitivity, especially of the skin); Exfoliation of the skin ofburning extremities (head, arms and feet), followed by“pins atrophy of the Cognitive small amounts), etc.; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and Diplopia (simultaneous perception of two images of a single object); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey needles”, numbness, itching or of the skin with no apparent cause); Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, x facial pallor, etc.; Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Loss of equilibrium/imbalance/unsteadiness; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; shoulder girdle, e.g., trapezii; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30urinating beatsofper6 of 11 Hypertrichosis (abnormal amount of hair growth over the body). feverishness (with/without fever), episodes of extreme sweating, etc.; Muscle tenderness: below the ribs; minute, or toDysfunction ≥120 beats perof minute) after standing still for a while (can be delayed); position sense of hands/fingers and feet/toes; Intolerance of extremes ofsimple temperature/hypersensitivity to climatic change; Clumsiness/fumble with manoeuvres; and Deafness. Sensory Dysfunction Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Diminished or absent vibration sense of hands/fingers and feet/toes; Abnormal dryness the skin of the extremities (head, arms and feet); Mental confusion. micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often Autonomic Cognitive Dysfunction small amounts), etc.; Diplopia (simultaneous perception of two images of a single object); Hyperalgesia (increased sensitivity to painful stimuli); skin and subcutaneous tissue; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey needles”, numbness, itching or burning of the skin with no apparent cause); accommodation (depth perception); Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, x equilibrium/imbalance/unsteadiness; facial pallor, etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability inper6 of 11 Hypoesthesia (reduced sense of touch or physical numbness); Table 3. Neurological symptoms of patients observed insensation/local and epidemic cases [1,3]. Loss of Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Hypoalgesia (decreased sensitivity to painful stimuli); Muscle tenderness: shoulder girdle, e.g., trapezii; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats feverishness (with/without fever), episodes of extreme sweating, etc.; Nystagmus (involuntary eye movements, “dancing eyes”); below the ribs; minute, or toDysfunction ≥120 beats per minute) after standing still for aendemic while (can be delayed); Intolerance of extremes of temperature/hypersensitivity to climatic change; Sensory Dysfunction Muscle tenderness: abdomen, e.g., abdominal recti; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Diminished or absent vibration sense of hands/fingers and feet/toes; Abnormal dryness of the skin of the extremities (head, arms and feet); Mental confusion. micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Hyperesthesia (excessive physical sensitivity, especially of the skin); Exfoliation of the skin ofsense extremities (head, arms and feet), followed by“pins atrophy of in the6 of 11 Autonomic Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and Cognitive Dysfunction small amounts), etc.; Motor pallor, Dysfunction Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Loss of accommodation (depth perception); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, xnails Brittle (onychorrhexis); and facial etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability Hypoesthesia (reduced of touch or physical sensation/local numbness); Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; equilibrium/imbalance/unsteadiness; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of calculation, using wrong words, forgetfulness, etc.); Hypoalgesia (decreased sensitivity to painful stimuli); Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per feverishness (with/without fever), episodes of extreme sweating, etc.; Diminished or absent position sense of hands/fingers and feet/toes; Muscle tenderness: below the ribs; minute, or toDysfunction ≥120 per minute) after standing still for atickling, while (can befeet); delayed); Intolerance of(abnormal extremes of to pollakiuria climatic change; Hyperacusis (intolerance oftemperature/hypersensitivity loud noise); abdomen, e.g., abdominal recti; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Abnormal dryness of the skin of the extremities (head, arms and Blurring ofbeats (near) vision; micturition, nocturia (wake at night one or more times to urinate), (often urinating Hyperesthesia (excessive physical sensitivity, especially of the skin); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Autonomic Paraesthesia sensations such as tingling, pricking, “pins and Cognitive Dysfunction small amounts), etc.; Hyperalgesia (increased sensitivity to painful stimuli); skin and subcutaneous tissue; needles”, numbness, itching or burning of the skin with no apparent cause); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, x facial pallor, etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability in Table 3.paralysis; Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Loss of equilibrium/imbalance/unsteadiness; Muscle tenderness: shoulder girdle, e.g., trapezii; Hypertrichosis (abnormal amount of hair growth over the body). Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of calculation, using wrong words, forgetfulness, etc.); Hypoalgesia (decreased sensitivity to painful stimuli); Nystagmus (involuntary eye movements, “dancing eyes”); Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per6 of 11 Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Complete Diminished or absent position sense of hands/fingers and feet/toes; minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Intolerance of extremes of temperature/hypersensitivity to climatic change; vibration sense of hands/fingers and feet/toes; Muscle tenderness: abdomen, e.g., abdominal recti; Bladder dysfunction: disturbance of micturition (urination), difficulty starting Abnormal dryness of the skin of the extremities (head, arms and feet); Tinnitus; and Blurring of (near) vision; micturition, nocturia (wake ator night one or more times to urinate), pollakiuria (often urinating Exfoliation of the skin ofburning extremities (head, arms and feet), followed byin atrophy of in the Diplopia (simultaneous perception of two images of a single object); Cognitive Dysfunction small amounts), etc.; Hyperalgesia (increased sensitivity to painful stimuli); skin and subcutaneous tissue; needles”, numbness, itching of the skin with no apparent cause); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Brittle nails (onychorrhexis); and Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Dizziness/giddiness/vertigo (when standing); Diagnostics 2018, 8, x facial pallor, etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Loss of equilibrium/imbalance/unsteadiness; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings ofper6 of 11 calculation, wrong words, forgetfulness, etc.); Nystagmus (involuntary eye movements, “dancing Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats Muscle tenderness: below the ribs; Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Paralysis of confusion. the limbs (arms and legs) Sensory Dysfunction Diminished or absent position sense ofof hands/fingers and feet/toes; Hyperacusis (intolerance of loud noise); minute, or tousing ≥120 beats per minute) after standing still for aeyes”); while (can be delayed); Intolerance of extremes of temperature/hypersensitivity to climatic change; Mental vibration sense hands/fingers and feet/toes; Bladder dysfunction: disturbance of micturition (urination), difficulty starting Abnormal dryness of the skin of the extremities (head, arms and feet); Hyperesthesia (excessive physical sensitivity, especially of the skin); Blurring of (near) vision; micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Exfoliation of the skin ofsense extremities (head, arms and followed byin atrophy of in the Deafness. Diplopia (simultaneous perception of two images of afeet), single object); Cognitive Dysfunction small amounts), etc.; skin and subcutaneous tissue; Loss of accommodation (depth perception); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Brittle nails (onychorrhexis); and Hypoesthesia (reduced of touch or physical sensation/local numbness); facial pallor, etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability shoulder girdle, e.g., trapezii; Hypertrichosis (abnormal amount of hair growth over the body). Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Hypoalgesia (decreased sensitivity to painful stimuli); Loss of equilibrium/imbalance/unsteadiness; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings ofper calculation, using wrong words, forgetfulness, etc.); Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30and beats Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Paralysis of confusion. the face; Hyperacusis (intolerance oftemperature/hypersensitivity loud noise); minute, or toDysfunction ≥120 beats per minute) after standing still for atickling, while (can be delayed); Muscle tenderness: abdomen, e.g., abdominal recti; Intolerance of extremes of to climatic change; Mental Diminished or absent vibration sense of hands/fingers and feet/toes; Tinnitus; and Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Abnormal dryness of the skin of the extremities (head, arms and feet); Hyperesthesia (excessive physical sensitivity, especially of the skin); Autonomic Paraesthesia (abnormal sensations such as tingling, pricking, “pins micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Hyperalgesia (increased sensitivity to painful stimuli); Diplopia (simultaneous perception of two images of a single object); Cognitive Dysfunction small amounts), etc.; skin and subcutaneous tissue; Loss of accommodation (depth perception); Motor Dysfunction Symptoms related to impaired circulation: cold extremities (hands, feet, cases etc.), ashen-grey Brittle (onychorrhexis); and Photophobia/defective response tostanding light (sluggish pupils)/light hypersensitivity; facial pallor, etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability in Muscle tenderness: shoulder girdle, e.g., trapezii; Hypertrichosis (abnormal amount of hair growth the body). Table 3.nails Neurological symptoms of patients observed inover and epidemic [1,3]. Hypoalgesia (decreased sensitivity to painful stimuli); Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of calculation, wrong words, forgetfulness, etc.); below the ribs; Sensory Dysfunction Diminished or absent position sense of hands/fingers and feet/toes; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Paralysis of swallowing; minute, or tousing ≥120 beats per minute) after still for aendemic while (can be delayed); Intolerance of extremes of temperature/hypersensitivity to climatic change; Mental confusion. Tinnitus; and Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Blurring of (near) vision; Abnormal dryness of the skin of the extremities (head, arms and feet); Hyperesthesia (excessive physical sensitivity, especially of the skin); Autonomic Dysfunction Deafness. micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Hyperalgesia (increased sensitivity to painful stimuli); needles”, numbness, itching or burning of the skin with no apparent cause); Cognitive Dysfunction small amounts), etc.; skin and subcutaneous tissue; Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Loss of accommodation (depth perception); Dizziness/giddiness/vertigo (when standing); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Brittle nails (onychorrhexis); and Photophobia/defective response tostanding light (sluggish pupils)/light hypersensitivity; facial pallor, etc.; Neurocognitive impairment (impaired memory orover concentration, impaired abilityof in Hypertrichosis (abnormal amount of hair growth the body). Nystagmus (involuntary eye movements, “dancing eyes”); Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings calculation, using wrong words, forgetfulness, etc.); Complete paralysis; Muscle tenderness: below the ribs; Sensory Dysfunction Diminished or absent position sense of hands/fingers and feet/toes; Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Poor movement of the soft palate; abdomen, e.g., abdominal recti; vibration sense of hands/fingers and feet/toes; minute, or to ≥120 beats per minute) after still for a while (can be delayed); Intolerance of extremes of temperature/hypersensitivity to climatic change; Mental confusion. Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Abnormal dryness of the skin of the extremities (head, arms and feet); Autonomic Dysfunction Deafness. Diplopia (simultaneous perception of two images of a single object); micturition, nocturia (wake atimpaired night one or more times to urinate), pollakiuria urinating Exfoliation of the skin of extremities (head, arms and feet), followed by(often atrophy of in the Hyperalgesia (increased sensitivity to painful stimuli); Cognitive Dysfunction small amounts), etc.; skin and subcutaneous tissue; Motor Dysfunction upper and limbs (arms and legs, e.g., gastrocnemii); Hypoesthesia (reduced sense oflower touch or physical sensation/local numbness); Dizziness/giddiness/vertigo (when standing); Symptoms related to circulation: cold extremities (hands, feet, etc.), ashen-grey Brittle (onychorrhexis); and Muscle tenderness: shoulder girdle, e.g., trapezii; Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Loss ofnails equilibrium/imbalance/unsteadiness; facial pallor, etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability Hypertrichosis (abnormal amount of hair growth over the body). Nystagmus (involuntary eye movements, “dancing eyes”); Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of calculation, using wrong words, forgetfulness, etc.); Sensory Dysfunction Hyperacusis (intolerance of loud noise); Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Paralysis the limbs (arms and legs) Muscle spasms (often in limbs); Muscle tenderness: abdomen, e.g., abdominal recti; Diminished or absent vibration sense of hands/fingers and feet/toes; Intolerance of extremes of temperature/hypersensitivity to climatic change; Mental confusion. Blurring ofof (near) vision; Hyperesthesia (excessive physical sensitivity, especially of the skin); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Abnormal dryness of the skin of the extremities (head, arms and feet); Autonomic Dysfunction needles”, numbness, itching or burning of the skin with no apparent cause); micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the small amounts), etc.; Loss of accommodation (depth perception); skin and subcutaneous tissue; Motor Dysfunction Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Dizziness/giddiness/vertigo (when standing); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Brittle nails (onychorrhexis); and shoulder girdle, e.g., trapezii; Hypoalgesia (decreased sensitivity to painful stimuli); Loss of equilibrium/imbalance/unsteadiness; facial pallor, etc.; Neurocognitive impairment (impaired memory or concentration, impaired ability in Hypertrichosis (abnormal amount ofofhair growth over the body). Complete paralysis; Muscle tenderness: below the ribs; Nystagmus (involuntary eye movements, “dancing eyes”); Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsofper Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings calculation, using wrong words, forgetfulness, etc.); Sensory Dysfunction Hyperacusis (intolerance of loud noise); Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes extreme sweating, etc.; Muscle twitches/jerking of the limbs/myoclonus; Tinnitus; and Intolerance of extremes of temperature/hypersensitivity to climatic change; Paralysis of the face; Mental confusion. Blurring of (near) vision; Hyperesthesia (excessive physical sensitivity, especially of the skin); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Abnormal dryness of the skin of the extremities (head, arms and feet); Diplopia (simultaneous perception of two images of a single object); Autonomic Dysfunction Hyperalgesia (increased sensitivity to painful stimuli); needles”, numbness, itching or burning of the skin with no apparent cause); micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Hypoesthesia (reduced sense of touch or physical sensation/local numbness); small amounts), etc.; skin and subcutaneous tissue; Dizziness/giddiness/vertigo (when standing); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Brittle nails (onychorrhexis); and Muscle tenderness: shoulder girdle, e.g., trapezii; Loss of equilibrium/imbalance/unsteadiness; facial pallor, etc.; Hypertrichosis (abnormal amount of hair growth over the body). Complete paralysis; below the ribs; Diminished or absent position sense of hands/fingers and feet/toes; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsofper Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings calculation, wrong words, forgetfulness, etc.); Paralysis of the limbs (arms and legs) Muscle tenderness: abdomen, e.g., abdominal recti; Sensory Dysfunction Hyperacusis (intolerance of loud noise); minute, or tousing ≥120 beats per minute) after standing still for aapparent while (can be delayed); Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Fasciculation of muscles (local, involuntary muscle contraction and relaxation); Tinnitus; and Intolerance of extremes of temperature/hypersensitivity to climatic change; Mental confusion. Deafness. Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Abnormal dryness of the skin of the extremities (head, arms and feet); Paralysis of swallowing; Diplopia (simultaneous perception of two images of a single object); Autonomic Dysfunction Hyperalgesia (increased sensitivity to painful stimuli); needles”, numbness, itching or burning of the skin with no cause); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the Loss of accommodation (depth perception); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); small amounts), etc.; skin and subcutaneous tissue; Dizziness/giddiness/vertigo (when standing); Hypoalgesia (decreased sensitivity to painful stimuli); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Brittle nails (onychorrhexis); and Loss of equilibrium/imbalance/unsteadiness; facial pallor, etc.; Nystagmus (involuntary eye movements, “dancing eyes”); Hypertrichosis (abnormal amount of hair growth over the body). Muscle tenderness: below the ribs; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsof per Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings Paralysis of the limbs (arms and legs) abdomen, e.g., abdominal recti; Diminished or absent vibration sense of hands/fingers and feet/toes; Sensory Dysfunction minute, or toDysfunction ≥120 beats per minute) after standing still for aapparent while (can be delayed); Clumsiness/fumble with simple manoeuvres; and feverishness (with/without fever), episodes of extreme sweating, etc.; Exaggerated tendon reflexes of the upper and lower limbs (increase in amplitude andstarting duration of face; Blurring of (near) vision; Tinnitus; and Bladder dysfunction: disturbance of micturition (urination), difficulty in Intolerance of extremes of temperature/hypersensitivity to climatic change; Mental confusion. Deafness. Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Abnormal dryness of the skin of the extremities (head, arms and feet); Autonomic needles”, numbness, itching or burning of the skin with no cause); Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of themuscle Motor Dysfunction Poor movement of the soft palate; Loss of accommodation (depth perception); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); skin and subcutaneous tissue; Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Dizziness/giddiness/vertigo (when standing); shoulder girdle, e.g., trapezii; Hypoalgesia (decreased sensitivity to painful stimuli); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Brittle nails (onychorrhexis); and Loss of equilibrium/imbalance/unsteadiness; Diminished or absent position sense of hands/fingers and feet/toes; facial pallor, etc.; Hypertrichosis (abnormal amount of hair growth over the body). Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Hyperacusis (intolerance of loud noise); contraction in response to an impulse); Muscle tenderness: abdomen, e.g., abdominal recti; Sensory Dysfunction minute, or toDysfunction ≥120 beats per minute) after standing stillespecially for aapparent while (can befeet); delayed); feverishness (with/without fever), episodes of extreme sweating, etc.; the face; Blurring of (near) vision; Hyperesthesia (excessive physical sensitivity, of the skin); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Intolerance of extremes of temperature/hypersensitivity to climatic change; Mental confusion. Paralysis of swallowing; Diplopia (simultaneous perception of two images of afeet), single object); Deafness. Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Abnormal dryness of the skin ofof the extremities (head, arms and Autonomic needles”, numbness, itching or burning the skin with no cause); Exfoliation of the skin of extremities (head, arms and followed by“pins atrophy of the Motor Dysfunction Hypoesthesia (reduced sense of touch or physical sensation/local numbness); skin and subcutaneous tissue; Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Dizziness/giddiness/vertigo (when standing); Muscle tenderness: shoulder girdle, e.g., trapezii; Hypoalgesia (decreased sensitivity to painful stimuli); Brittle nails (onychorrhexis); and Complete paralysis; Nystagmus (involuntary eye movements, “dancing eyes”); Loss of equilibrium/imbalance/unsteadiness; below the ribs; Diminished or absent position sense of hands/fingers and feet/toes; facial pallor, etc.; Hypertrichosis (abnormal amount of hair growth over the body). Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per vibration sense of hands/fingers and feet/toes; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Sensory Dysfunction minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); feverishness (with/without fever), episodes of extreme sweating, etc.; Tinnitus; and Blurring of (near) vision; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Intolerance of extremes of temperature/hypersensitivity to climatic change; Paralysis of swallowing; Diplopia (simultaneous perception of two images of afeet), single object); Hyperalgesia (increased sensitivity to painful stimuli); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and micturition, nocturia (wake ator night one or more times to(head, urinate), pollakiuria (often urinating Abnormal dryness of the skin ofperception); the extremities arms and feet); Autonomic Dysfunction Poor movement of the soft palate; Loss of accommodation (depth needles”, numbness, itching burning of the skin with no apparent cause); small amounts), etc.; Exfoliation of the skin of extremities (head, arms and followed by“pins atrophy of the Motor Dysfunction Hypoesthesia (reduced sense of touch or physical sensation/local numbness); skin and subcutaneous tissue; Dizziness/giddiness/vertigo (when standing); Hypoalgesia (decreased sensitivity to painful stimuli); Brittle nails (onychorrhexis); and Complete paralysis; Nystagmus (involuntary eye movements, “dancing eyes”); Loss of equilibrium/imbalance/unsteadiness; Muscle tenderness: below the ribs; Diminished or absent position sense of hands/fingers and feet/toes; Hypertrichosis (abnormal amount of hair growth over the body). Paralysis of the limbs (arms and legs) Hyperacusis (intolerance of loud noise); Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per abdomen, e.g., abdominal recti; vibration sense of hands/fingers and feet/toes; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Sensory Dysfunction minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Hyperesthesia (excessive physical sensitivity, especially of the skin); feverishness (with/without fever), episodes of extreme sweating, etc.; Bladder dysfunction: disturbance of (urination), difficulty in starting Intolerance of(abnormal extremes of temperature/hypersensitivity to pollakiuria climatic change; Deafness. Diplopia (simultaneous perception ofmicturition two images of afeet), single object); Paraesthesia sensations such as tingling, tickling, pricking, and micturition, nocturia (wake ator night one or more times to urinate), (often urinating Abnormal dryness of the skin of the extremities (head, arms and feet); Poor movement of the soft palate; Loss of accommodation (depth perception); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); needles”, numbness, itching burning of the skin with no apparent cause); small amounts), etc.; Exfoliation of the skin of extremities (head, arms and followed by“pins atrophy of the Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Hypoesthesia (reduced sense of touch or physical sensation/local numbness); skin and subcutaneous tissue; Dizziness/giddiness/vertigo (when standing); Hypoalgesia (decreased sensitivity to painful stimuli); Brittle nails (onychorrhexis); and Complete paralysis; Loss of equilibrium/imbalance/unsteadiness; Diminished or absent position sense of hands/fingers and feet/toes; Hypertrichosis (abnormal amount of hair growth over the body). Paralysis of the limbs (arms and legs) Hyperacusis (intolerance of loud noise); Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per Muscle tenderness: abdomen, e.g., abdominal recti; vibration sense of hands/fingers and feet/toes; face; Tinnitus; and Sensory Dysfunction minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Blurring of (near) vision; Hyperesthesia (excessive physical sensitivity, especially of the skin); feverishness (with/without fever), episodes of extreme sweating, etc.; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Hyperalgesia (increased sensitivity toextremities painful stimuli); Intolerance of(abnormal extremes of temperature/hypersensitivity to pollakiuria climatic change; Paraesthesia sensations such as tingling, tickling, pricking, and micturition, nocturia (wake ator night one or more times to urinate), (often urinating Abnormal dryness of the skin of the (head, arms and feet); Motor Dysfunction Loss of accommodation (depth perception); needles”, numbness, itching burning of the skin with no apparent cause); small amounts), etc.; Exfoliation of the skin of extremities (head, arms and feet), followed by“pins atrophy of the Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Muscle tenderness: shoulder girdle, trapezii; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Hypoesthesia (reduced sense of touch or physical sensation/local numbness); skin and subcutaneous tissue; Nystagmus (involuntary eye movements, “dancing eyes”); Hypoalgesia (decreased sensitivity toe.g., painful stimuli); facial pallor, etc.; Brittle nails (onychorrhexis); and Loss of equilibrium/imbalance/unsteadiness; Diminished or absent position sense of hands/fingers and feet/toes; Hypertrichosis (abnormal amount of hair growth over the body). Paralysis of the limbs (arms and legs) Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per vibration sense of hands/fingers and feet/toes; face; Tinnitus; and Sensory Dysfunction minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Blurring of (near) vision; Hyperesthesia (excessive physical sensitivity, especially of the skin); Paralysis of swallowing; Deafness. Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Diplopia (simultaneous perception of two images of a single object); Hyperalgesia (increased sensitivity to painful stimuli); Intolerance of extremes of temperature/hypersensitivity to climatic change; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and micturition, nocturia (wake ator night one or more times to urinate), pollakiuria (often urinating Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Abnormal dryness of the skin of the (head, arms and feet); needles”, numbness, itching burning of the skin with no apparent cause); small amounts), etc.; Exfoliation of the skin of extremities (head, arms and feet), followed by“pins atrophy ofof the Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Hypoesthesia (reduced sense of touch or physical sensation/local numbness); skin and subcutaneous tissue; Complete paralysis; Nystagmus (involuntary eye movements, “dancing eyes”); Muscle tenderness: the ribs; Hypoalgesia (decreased sensitivity toextremities painful stimuli); facial pallor, etc.; Brittle nails (onychorrhexis); and Hyperacusis (intolerance of loud noise); Symptoms related tobelow thermoregulation: feeling cold, chills, hypothermia, feelings Diminished or absent position sense of hands/fingers and feet/toes; Hypertrichosis (abnormal amount of hair growth over the body). Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beats per vibration sense of hands/fingers and feet/toes; the face; Sensory Dysfunction minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Hyperesthesia (excessive physical sensitivity, especially of the skin); Paralysis of swallowing; Deafness. Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Diplopia (simultaneous perception of two images of a single object); Hyperalgesia (increased sensitivity to painful stimuli); Poor movement of the soft palate; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and Motor Dysfunction micturition, nocturia (wake ator night one or more times to urinate), pollakiuria (often urinating Loss ofnails accommodation (depth perception); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Abnormal dryness of the skin of the extremities (head, arms and feet); needles”, numbness, itching of the skin with no apparent cause); small amounts), etc.; shoulder girdle, e.g., trapezii; Exfoliation of the skin ofburning extremities (head, arms and feet), followed by“pins atrophy ofof the Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Hypoesthesia (reduced sense of touch or physical sensation/local numbness); skin and subcutaneous tissue; Nystagmus (involuntary eye movements, “dancing eyes”); Hypoalgesia (decreased sensitivity to painful stimuli); facial pallor, etc.; Brittle (onychorrhexis); and Paralysis of the limbs (arms and legs) Hyperacusis (intolerance of loud noise); Muscle tenderness: abdomen, e.g., abdominal recti; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings position sense of hands/fingers and feet/toes; Hypertrichosis (abnormal amount of hair growth over the body). Tinnitus; and Diminished or absent vibration sense of hands/fingers and feet/toes; feverishness (with/without fever), episodes of extreme sweating, etc.; Sensory Dysfunction minute, or tonocturia ≥120 beats per minute) after standing stillespecially for aapparent while (can be delayed); Hyperesthesia (excessive physical sensitivity, of pollakiuria the skin); Paralysis of swallowing; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Hyperalgesia (increased sensitivity to painful stimuli); Poor movement of the soft palate; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, and Motor Dysfunction micturition, (wake at night one or more times to urinate), (often urinating Loss of accommodation (depth perception); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); needles”, numbness, itching or burning of the skin with no cause); small amounts), etc.; Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; shoulder girdle, e.g., trapezii; Exfoliation of the skin of extremities (head, arms and feet), followed by“pins atrophy ofof the Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Complete paralysis; Muscle tenderness: below the ribs; skin and subcutaneous tissue; Hypoalgesia (decreased sensitivity to painful stimuli); facial pallor, etc.; Brittle nails (onychorrhexis); and Hyperacusis (intolerance of loud noise); Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings Diminished or absent position sense of hands/fingers and feet/toes; Hypertrichosis (abnormal amount of hair growth over the body). Paralysis of the face; Tinnitus; and Blurring of (near) vision; vibration sense of hands/fingers and feet/toes; feverishness (with/without fever), episodes of extreme sweating, etc.; Sensory Dysfunction Deafness. Hyperesthesia (excessive physical sensitivity, especially of the skin); Intolerance of extremes of temperature/hypersensitivity to climatic change; Bladder dysfunction: disturbance of micturition (urination), difficulty in starting Hyperalgesia (increased sensitivity to painful stimuli); Poor movement of the soft palate; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); needles”, numbness, itching or burning of the skin with no apparent cause); small amounts), etc.; Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; shoulder girdle, e.g., trapezii; Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Complete paralysis; Nystagmus (involuntary eye movements, “dancing eyes”); Muscle tenderness: below the ribs; skin and subcutaneous tissue; Hypoalgesia (decreased sensitivity to painful stimuli); facial pallor, etc.; Paralysis of the limbs (arms and legs) abdomen, e.g., abdominal recti; Brittle nails (onychorrhexis); and Symptoms related to thermoregulation: feeling cold, hypothermia, feelings of Diminished or absent position sense of hands/fingers and feet/toes; Hypertrichosis (abnormal amount of hair growth over the body). Tinnitus; and vibration sense of hands/fingers and feet/toes; feverishness (with/without fever), episodes of extreme sweating, etc.; Sensory Dysfunction Paralysis of swallowing; Deafness. Diplopia (simultaneous perception of two images ofapparent achills, single object); Hyperesthesia (excessive physical sensitivity, especially of the skin); Intolerance of extremes of temperature/hypersensitivity to climatic change; Hyperalgesia (increased sensitivity to painful stimuli); Abnormal dryness of the skin of the extremities (head, arms and feet); Motoramounts), Dysfunction Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and micturition, nocturia (wake ator night one or more times to urinate), pollakiuria (often urinating Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); needles”, numbness, itching burning of the skin with no cause); small etc.; shoulder girdle, e.g., trapezii; Symptoms to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Nystagmus (involuntary eye movements, “dancing eyes”); Muscle tenderness: below the ribs; Hypoalgesia (decreased sensitivity to painful stimuli); facial pallor, etc.; Paralysis ofrelated the limbs (arms and legs) Hyperacusis (intolerance of loud noise); abdomen, e.g., abdominal recti; Brittle nails (onychorrhexis); and Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Diminished or absent position sense of hands/fingers and feet/toes; face; Blurring of (near) vision; Hypertrichosis (abnormal amount of hair growth over the body). vibration sense of hands/fingers and feet/toes; feverishness (with/without fever), episodes of extreme sweating, etc.; Sensory Dysfunction Deafness. Hyperesthesia (excessive physical sensitivity, especially of the skin); Intolerance of extremes of temperature/hypersensitivity to climatic change; Poor movement of the soft palate; Loss of accommodation (depth perception); Hyperalgesia (increased sensitivity toextremities painful stimuli); Abnormal dryness of the skin thesuch (head, armse.g., andgastrocnemii); feet); Motor Dysfunction Paraesthesia as tingling, tickling, pricking, and of the Muscle tenderness: upper and of lower limbs (arms and legs, Exfoliation of(abnormal the skin ofsensations extremities (head, arms and feet), followed by“pins atrophy
Diagnostics 2018, 8, x
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Diagnostics 2018, 8,3. x Diagnostics Table 2018, 8, 64Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Diagnostics 2018, 8, x
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Cognitive Dysfunction Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Diagnostics 2018, 8,3. x Neurological Table symptoms(impaired of patients observed in concentration, endemic and epidemic cases [1,3]. Neurocognitive impairment memory or impaired ability Table 3. Cont. Cognitive Dysfunction Diagnostics 2018, 8, x calculation, using wrong words, forgetfulness, etc.);
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Cognitive Dysfunction Table 3. Neurological symptoms(impaired of patientsmemory observedor in concentration, endemic and epidemic cases [1,3]. in Neurocognitive impairment impaired ability Clumsiness/fumble with simple and Depressed tendon reflexes of the upper manoeuvres; and lower limbs (decrease in amplitude and duration of muscle Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. in Neurocognitive impairment (impaired memory or concentration, impaired ability calculation, using wrong words, forgetfulness, etc.); contraction in response to an impulse); Mental confusion. Cognitive Dysfunction Diagnostics 2018, 8, x 6 of 11 calculation, using wrong words, forgetfulness, etc.); and Clumsiness/fumble with simple manoeuvres; Extensor plantar responses (Babinski reflex); Autonomic Dysfunction Cognitive Dysfunction Diagnostics 2018, 8, x 11 Neurocognitive impairment (impaired memory or concentration, impaired ability in 6 ofby Clumsiness/fumble with simple manoeuvres; and Ankle clonus (series of involuntary, rhythmic, muscular contractions and relaxations usually initiated Mental confusion. Diagnostics 2018, 8, x 6 of 11 Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Dizziness/giddiness/vertigo (when standing); Neurocognitive impairment (impaired memory or concentration, impaired ability in calculation, using wrong words, forgetfulness, etc.); a reflex); Mental confusion. Autonomic Dysfunction Table 3. Neurological symptoms of patients observed in endemic and epidemic cases [1,3]. Loss(lack of equilibrium/imbalance/unsteadiness; calculation, using words, etc.);including Clumsiness/fumble with simplemovements, manoeuvres; and gait abnormality); and Ataxia ofwrong coordination of forgetfulness, muscle Cognitive Dysfunction Autonomic Dysfunction Table 3. Neurological symptoms of patients observed Dizziness/giddiness/vertigo (when standing); Postural orthostatic tachycardia (POTS): an abnormal heart and rateepidemic increasecases (≥30 [1,3]. beats per Clumsiness/fumble with simple manoeuvres; andin endemic Tendency to stumble when walking, unsteady gait. Mental confusion. Cognitive Dysfunction impairment (when Neurocognitive (impaired memory or concentration, impaired ability in Dizziness/giddiness/vertigo standing); Loss of equilibrium/imbalance/unsteadiness; minute, or to ≥120 beats per minute) after standing still for a while (can be delayed); Mental confusion. Autonomic Dysfunction Cognitive Dysfunction Unclassified Symptoms Neurocognitive (impaired memory or concentration, impaired ability calculation, using wrongimpairment words, forgetfulness, etc.); LossNeurological of equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsinper Bladder dysfunction: disturbance ofstanding); micturition (urination), difficulty in starting Autonomic Dysfunction Dizziness/giddiness/vertigo (when Neurocognitive impairment (impaired memory or concentration, impaired ability calculation, wrong words, forgetfulness, etc.); Clumsiness/fumble with simple manoeuvres; and Reversal of sleep rhythm (not sleepy at (POTS): night, sleeping infor theaday); Postural orthostatic tachycardia anstill abnormal heart(can rate be increase (≥30 beatsinper minute, or tousing ≥120 beats per minute) after while delayed); micturition, nocturia (wake at night one orstanding more times to urinate), pollakiuria (often urinating Dizziness/giddiness/vertigo (when standing); Loss of equilibrium/imbalance/unsteadiness; calculation, using wrong words, forgetfulness, etc.); Clumsiness/fumble simple manoeuvres; Vivid (often in after colour); and Mental confusion. minute, or dreams/nightmares to ≥120 beats per with minute) standing stilland for a while (can be delayed); Bladder dysfunction: disturbance of micturition (urination), difficulty in starting smallHeadaches amounts), etc.; Loss of (often equilibrium/imbalance/unsteadiness; Postural orthostatic tachycardia (POTS): an abnormal rate increase (≥30 beats per Clumsiness/fumble with simplesometimes manoeuvres; and frontal or occipital, accentuated byheart movement). Mental confusion. Autonomic Dysfunction Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating Symptoms related totachycardia impaired circulation: extremities (hands, feet, etc.), Postural orthostatic (POTS): ancold abnormal heart(can rate be increase (≥30 ashen-grey beats per minute, or to ≥120 beats per minute) after standing still for a while delayed); Mental confusion. Autonomic Dysfunction micturition, nocturia (wake at night one or more times to urinate), pollakiuria (often urinating small amounts), etc.; Dizziness/giddiness/vertigo (when standing); facial pallor, etc.; minute, Bladder or toDysfunction ≥120 beats per minute) after standing still for a while (can be delayed); dysfunction: disturbance ofof micturition (urination), difficulty in starting Autonomic smallME amounts), etc.; Dizziness/giddiness/vertigo (when standing); 3.2.3. Often with a Number Symptoms Related Other feet, Body Systems Symptoms related to circulation: cold cold, extremities (hands, etc.), ashen-grey Loss of Coincides equilibrium/imbalance/unsteadiness; Symptoms related toatimpaired thermoregulation: feeling chills,to hypothermia, feelings of Bladder dysfunction: disturbance of micturition (urination), difficulty in starting micturition, nocturia (wake night one or more times to urinate), pollakiuria (often urinating Dizziness/giddiness/vertigo (when standing); Symptoms related totachycardia impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Loss of equilibrium/imbalance/unsteadiness; facial pallor, etc.; Postural orthostatic (POTS): an abnormal heart rate increase (≥30 beats per feverishness (with/without fever), episodes of extreme sweating, etc.; In amounts), addition to the(wake two mandatory post-exertional micturition, nocturia at night onefeatures, or moremuscle times tofatigability/prolonged urinate), pollakiuria (often urinating muscle small etc.; Loss of equilibrium/imbalance/unsteadiness; facial pallor, Postural orthostatic anstill abnormal heart(can rate be increase (≥30 beatsofper Symptoms related thermoregulation: feeling cold, chills, hypothermia, feelings minute, or toetc.; ≥120 beats pertotachycardia minute) after(POTS): standing for a while delayed); Intolerance of extremes of temperature/hypersensitivity to climatic change; small amounts), etc.; weakness after and neurological dysfunction, ME patients often, but not always, suffer from many Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey Postural orthostatic tachycardia (POTS): an abnormal heart rate increase (≥30 beatsofper Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings minute, Bladder or to(with/without ≥120 beats perfever), minute) after standing stillsweating, for a while (can be delayed); feverishness episodes extreme etc.; dysfunction: disturbance ofof micturition (urination), difficulty in starting Abnormal dryness of the skin of the extremities (head, arms and feet); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey other symptoms related to bodily including symptoms, e.g., myalgia, facial pallor, etc.; minute, or tonocturia ≥120 beats perother minute) aftersystems, stillsweating, for a musculoskeletal while (can be delayed); feverishness (with/without fever), episodes of extreme etc.; Bladder dysfunction: disturbance ofmore micturition (urination), difficulty in starting Intolerance of(wake extremes ofextremities temperature/hypersensitivity to climatic change; micturition, at night one orstanding times to urinate), pollakiuria (often urinating Exfoliation of the skin of (head, arms and feet), followed by atrophy oftender the facial pallor, etc.; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of paresis (without exercise) and joint pain, immunological symptoms, e.g., sore throat, Bladder dysfunction: ofmore micturition (urination), difficulty in starting Intolerance of(wake extremes ofskin temperature/hypersensitivity to pollakiuria climatic change; micturition, nocturia atdisturbance night one times to(head, urinate), (often urinating lymph Abnormal dryness of the of or the extremities arms and feet); small amounts), etc.; skin and subcutaneous tissue; Symptoms related to feeling cold, chills, hypothermia, feelingsdiarrhoea of feverishness (with/without fever), episodes of extreme sweating, etc.; nodes, and lymphadenopathy, symptoms, e.g., nausea, anorexia, and micturition, nocturia (wake atthermoregulation: night one or times to urinate), pollakiuria (often Abnormal dryness of the skin of themore extremities (head, arms and feet); small amounts), etc.; Exfoliation of the skin ofgastro-intestinal extremities (head, arms and feet), followed by atrophy of the Symptoms to impaired circulation: cold extremities (hands, feet, etc.),urinating ashen-grey Brittle nailsrelated (onychorrhexis); and feverishness (with/without fever), episodes of extreme sweating, etc.; Intolerance of extremes of temperature/hypersensitivity to climatic change; abdominal pain, e.g., respiratory distress, intercostal myalgia (often made small amounts), etc.; Exfoliation ofrespiratory the skin of symptoms, extremities (head, armsextremities and feet), followed by atrophy of the Symptoms related to impaired circulation: cold (hands, feet, etc.), ashen-grey skin and subcutaneous tissue; facial pallor, etc.;and Hypertrichosis (abnormal amount ofextremities hair growth(head, over the Intolerance of extremes ofskin temperature/hypersensitivity to body). climatic change; Abnormal dryness of the of the arms and feet); Symptoms related to impaired circulation: cold extremities (hands, feet, etc.), ashen-grey worse on breathing) and exertional chest pain with or without palpitations. ME patients can skin and subcutaneous tissue; facial pallor, etc.; Brittle nailsrelated (onychorrhexis); and to thermoregulation: feeling cold, chills, hypothermia, feelings of experience SensorySymptoms Dysfunction Abnormal dryness of the skin of the extremities (head, armsfollowed and feet); Exfoliation of the skin of extremities (head, arms and feet), byand atrophy ofof the strain [1], facial pallor, etc.; “extreme exhaustion”/”gross fatigue” physical or cognitive exertion emotional Brittle nailsrelated (onychorrhexis); andafter Symptoms to thermoregulation: feeling cold, chills, hypothermia, feelings Hypertrichosis (abnormal amount ofofhair growth over theetc.; body). feverishness (with/without fever), episodes extreme sweating, Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Exfoliation of the skin of extremities (head, arms and feet), followed by atrophy of the skin and subcutaneous tissue; Symptoms related to thermoregulation: feeling cold, chills, hypothermia, feelings of Hypertrichosis (abnormal amount ofofhair growth over the body). but looking at (with/without the definitions [2–4] symptoms reported [1,3], the abstract concept of post-exertional feverishness fever), episodes extreme sweating, etc.; Intolerance of extremes of and temperature/hypersensitivity to climatic change; Sensory Dysfunction needles”, numbness, itching or burning of the skin with no apparent cause); skin and subcutaneous tissue; Brittle nails (onychorrhexis); and feverishness (with/without fever), episodes of extremefeature sweating, etc.; Intolerance of(abnormal extremes temperature/hypersensitivity to climatic change; Sensory Dysfunction “malaise” [11,13], cannot beof considered mandatory for the diagnosis of ME Abnormal dryness theof skin ofathe extremities (head, arms and feet); Paraesthesia sensations such tingling, tickling, pricking, “pins and[1–4]. Hypoesthesia (reduced sense of touch orasphysical sensation/local numbness); Brittle nails of (onychorrhexis); and Hypertrichosis (abnormal amount ofextremities hair growth(head, over the body). Intolerance extremes of temperature/hypersensitivity to climatic change; Abnormal dryness of the skin of the arms and feet); Exfoliation the skin extremities (head, armsno and feet), followed atrophy Paraesthesia sensations such as tingling, tickling, pricking, and of the needles”, numbness,of(abnormal itching orofburning of the skin with apparent cause); by“pins Hypoalgesia (decreased sensitivity toextremities painful stimuli); Hypertrichosis (abnormal amount of hair growth over the body). Sensory Dysfunction 3.2.4. ME Is Often Accompanied by Emotional Problems, but Is Not Caused Those of Symptoms dryness oforthe skin ofof the arms and feet); Exfoliation ofitching the skin ofburning extremities (head, arms(head, and feet), followed byby atrophy the skin andAbnormal subcutaneous tissue; needles”, numbness, the skin with no apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Diminished or absent position sense of hands/fingers and feet/toes; SensoryExfoliation Dysfunction Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and of the skin of extremities (head, arms and feet), followed by atrophy of the skin andBrittle subcutaneous tissue; nails (onychorrhexis); and Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Hypoalgesia (decreased sensitivity to of painful stimuli); Emotional lability is a characteristic feature oftingling, ME [1–4]. According to the lastand patient population Diminished or absent vibration sense hands/fingers and feet/toes; Paraesthesia (abnormal sensations such as tickling, pricking, “pins needles”, numbness, itching or burning of the skingrowth with noover apparent cause); skin andBrittle subcutaneous tissue; nails (onychorrhexis); and (abnormal amount of hair the feet/toes; body). Hypoalgesia (decreased sensitivity toof painful stimuli); Diminished absent position sense hands/fingers and study [3],Hypertrichosis 98% of the or 420 ME or patients reported experiencing “emotional disability”. Other emotional Hyperesthesia (excessive physical sensitivity, especially of the skin); needles”, numbness, itching burning of the skin with noover apparent cause); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Brittle nails (onychorrhexis); and Hypertrichosis (abnormal amount of hair growth the body). Sensory Dysfunction Diminished or absent position sense of hands/fingers and feet/toes; vibration sense of hands/fingers and feet/toes; symptoms reported in cases ofsense ME [4] include of irritability“, impatience, anxiety, and Hyperalgesia (increased sensitivity tohair painful stimuli); Hypoesthesia (reduced of touch or “outbursts physical sensation/local numbness); Hypoalgesia (decreased sensitivity to painful stimuli); (abnormal amount of growth over the body). SensoryHypertrichosis Dysfunction Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and depression. However, it should be emphasized that “emotional lability” Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hypoalgesia (decreased sensitivity toofpainful stimuli);and feet/toes; and other psychological Diminished or absent position sense hands/fingers Sensory Dysfunction Hyperesthesia (excessive physical sensitivity, especially of the skin); “pins and Paraesthesia (abnormal sensations such as tingling, tickling, pricking, Hyperalgesia (increased sensitivity to painful stimuli); needles”, numbness, itching or burning of the skin with no apparent cause); Muscle tenderness: shoulder e.g., trapezii; sequels are caused byorME (likely duegirdle, tosense cerebral dysfunction), and do not cause the symptoms. Diminished absent position ofofhands/fingers and feet/toes; sense hands/fingers and feet/toes; Paraesthesia (abnormal sensations such as tingling, tickling, pricking, “pins and Hyperalgesia (increased sensitivity tolimbs painful stimuli); needles”, numbness, itching orvibration burning of the skin with no apparent cause); Muscle tenderness: upper and lower (arms and legs, e.g., gastrocnemii); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Muscle tenderness: below the ribs; Diminished or absent vibration sense of hands/fingers and feet/toes; Hyperesthesia (excessive physical sensitivity, especially of the skin); needles”, numbness, itching or burning of the skin with no apparent cause); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Hypoesthesia (reduced sense of touch or trapezii; physical sensation/local numbness); shoulder girdle, Hypoalgesia (decreased sensitivity toe.g., painful stimuli); 3.3. An Operational Definition of ME Muscle tenderness: abdomen, e.g., sensitivity, abdominal recti; Hyperesthesia (excessive physical especially of the skin); Hyperalgesia (increased sensitivity to painful stimuli); Hypoesthesia (reduced sense of touch or physical sensation/local numbness); Muscle tenderness: shoulder girdle, e.g., trapezii; Hypoalgesia (decreased sensitivity to painful stimuli); below the ribs; Diminished or absent position sense of hands/fingers and feet/toes; Blurring of (near) vision; Hyperalgesia (increased sensitivity to painful stimuli); Muscle tenderness: upper and lower limbs (arms and legs, e.g., gastrocnemii); Considering the descriptions, definitions [3,4], the symptoms experienced by 420 patients [3], Hypoalgesia (decreased sensitivity toofof painful stimuli); Muscle tenderness: below the ribs; Diminished or absent position sense hands/fingers abdomen, e.g., abdominal recti;of aand vibration sense hands/fingers andfeet/toes; feet/toes; Diplopiatenderness: (simultaneous perception of two images single object); Muscle upper and lower limbs (arms and legs, e.g., gastrocnemii); shoulder girdle, e.g., trapezii; and the symptoms in endemic and epidemic casesand ofofME [1], a discriminative operational Diminished or (excessive absent position sense ofof hands/fingers feet/toes; Muscle tenderness: abdomen, e.g., abdominal recti; vibration sense hands/fingers and feet/toes; Blurring ofobserved (near) vision; Hyperesthesia physical sensitivity, especially the skin); Loss of accommodation (depth perception); tenderness: shoulder e.g., trapezii; below thegirdle, ribs; definitionMuscle encompasses four (mandatory) features: Diminished or absent vibration sense of hands/fingers and feet/toes; Blurring of (near) vision; Hyperesthesia (excessive physical sensitivity, especially of the skin); Diplopia (simultaneous perception of images of a single object); Hyperalgesia (increasedresponse sensitivity to two painful stimuli); Photophobia/defective to abdominal light (sluggish pupils)/light hypersensitivity; Muscle tenderness: belowphysical the ribs; abdomen, e.g., recti;of Hyperesthesia (excessive sensitivity, especially of the skin); Diplopia (simultaneous perception of two images alegs, single object); Hyperalgesia (increased sensitivity tolimbs painful stimuli); Loss of accommodation (depth perception); Muscle tenderness: upper and lower (arms and e.g., gastrocnemii); Nystagmus (involuntary eye movements, “dancing eyes”); 1. muscle fatigability/prolonged muscle weakness after trivial exertion; Muscle tenderness: abdomen, e.g., abdominal recti; Blurring of (near) vision; Hyperalgesia (increased sensitivity to painful stimuli); Loss of accommodation (depth perception); Muscle tenderness: upper andgirdle, lower limbs (arms and legs, e.g., hypersensitivity; gastrocnemii); Photophobia/defective response to light (sluggish pupils)/light shoulder e.g., trapezii; Hyperacusis (intolerance ofTable loud noise); Blurring of (near) vision; 2. neurological disturbance (see 3):light Diplopia (simultaneous perception of two images of alegs, single object); Muscle tenderness: upper and lower limbs (arms and e.g., gastrocnemii); Photophobia/defective response to (sluggish pupils)/light hypersensitivity; shoulder girdle, e.g., trapezii; Nystagmus (involuntary eye movements, “dancing eyes”); Muscle tenderness: below the ribs; Tinnitus; and Diplopia (simultaneous perception of twotrapezii; images of a single object); Loss of accommodation (depth perception); Muscle tenderness: shoulder girdle, e.g., Nystagmus (involuntary eye movements, “dancing eyes”); below the ribs; Hyperacusis (intolerance of loud noise); Muscle tenderness: abdomen, e.g., abdominal recti; Deafness. accommodation (depth perception); a. Loss at of least one symptom related to cognitive dysfunction orhypersensitivity; one unclassified neurological Photophobia/defective response to light (sluggish pupils)/light Muscle tenderness: below the ribs; Hyperacusis (intolerance of loud noise); abdomen, e.g., abdominal recti; Tinnitus; and Blurring of (near) vision; Motor Dysfunction Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eye movements, “dancing symptom; Muscle tenderness: abdomen, e.g., abdominal recti;ofeyes”); Tinnitus; and Blurring of (near) vision; Deafness. Diplopia (simultaneous perception of two images a single object); Complete paralysis; Nystagmus (involuntary eye movements, “dancing eyes”); and Hyperacusis (intolerance of loud noise); b. at least one symptom related to autonomic dysfunction; Blurring of (near) vision; Deafness. Diplopia (simultaneous perception of two images of a single object); Loss of accommodation (depth perception); Motor Dysfunction Paralysis(simultaneous of the limbs (arms and legs) Hyperacusis (intolerance of loud noise); Tinnitus; and Diplopia perception ofsensory two images of a single object); c. Dysfunction at least two symptoms related dysfunction; Loss of accommodation (depth perception); Motor Photophobia/defective response toto light (sluggish pupils)/light hypersensitivity; Complete paralysis; Paralysis of the face; Tinnitus; and Deafness. Loss of accommodation (depth perception); Photophobia/defective response to light (sluggish pupils)/light hypersensitivity; Nystagmus (involuntary eyeand movements, “dancing eyes”); Completeof paralysis; Paralysis the limbs (arms legs) Paralysis swallowing; 3.Motor fluctuation ofof symptoms (within and between “episodes”); and hypersensitivity; Deafness. Dysfunction Photophobia/defective response to light (sluggish pupils)/light Nystagmus (involuntary eye movements, “dancing eyes”); Hyperacusis (intolerance of loud noise); limbs (arms and legs) Paralysis of the face; Poor movement of the soft palate; Dysfunction 4.Motor a prolonged relapsing course. Complete paralysis; Nystagmus (involuntary eye movements, Hyperacusis (intolerance of loud noise); “dancing eyes”); Tinnitus; the face; Paralysis and of swallowing; Complete paralysis; Paralysis of the limbs (arms and legs) Hyperacusis (intolerance of loud noise); and Deafness. Paralysis of swallowing; Poor movement of the the soft basic palate;requirements to comply with the diagnosis of ME [3,4]. ThisTinnitus; definition contains Paralysis of the limbs (arms and legs) Tinnitus; and face; Deafness. Motor Dysfunction Poor movement of the soft palate; The tentative caseofdefinition Paralysis the face; described above should be used in conjunction with a full clinical swallowing; Deafness. Motor Dysfunction Complete paralysis; assessment, with consideration of differential diagnoses. Paralysis of swallowing; Poor movement of the soft palate; Motor Dysfunction Complete paralysis; Paralysis of the limbs (arms and legs) Poor movement of the soft palate; Complete paralysis; Paralysis of the limbs face; (arms and legs) Paralysis limbs face; (arms and legs) Paralysis of of the swallowing; Paralysis of the face; swallowing; Poor movement of the soft palate; Paralysis of swallowing; Poor movement of the soft palate; Poor movement of the soft palate;
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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 [1–4], 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. 4. Discussion ME is a distinct neuromuscular disease with specific features [1–4]. Based on the definitions, ME is not an equivalent of CFS [11], an ill-defined fatigue syndrome. This observation is completely independent of the question whether the name “ME” is appropriate or not [31]. The discussion with regard to the definition (case criteria) should be separated from the discussion with regard to the most accurate label. Since the cause of ME [1–4] is yet unknown, the operational definition of ME proposed in this article still depends on self-report of symptoms. However, various symptoms, including muscle fatigability/prolonged muscle weakness (the distinctive symptom) and several neurological symptoms, can be assessed with objective tests. In 2011 a panel of experts proposed using the International Consensus Criteria (ICC) for ME [30]. The definition of the ME-ICC [30] deviates at different points from the original definition of ME [3,4]. Long-lasting post-exertional muscle weakness is an optional feature of ME according to the ICC [30], but is mandatory for diagnosis according to the original definition [3,4]. On the other hand, diagnosis as per the ME-ICC [30] requires several symptoms which were not part of the original definition of ME [3,4]. Future surveys using the operational definition of ME proposed here should make clear how big the overlap is between the original definition of ME [3,4] and that of the ME-ICC [30] and whether the latter can adequately replace the former according to the original criteria or not. According to the definition of “ME/CFS” proposed by the Institute of Medicine (now the National Academy of Medicine) in 2015 [13], post-exertional “malaise” is a differential feature of “ME/CFS” (in addition to fatigue and unrefreshing sleep). However, post-exertional “malaise”, an ill-defined notion, has never been described as a distinctive feature of ME [1–4] in the literature. Long-lasting post-exertional muscle weakness, the distinguishing feature of ME [1–4], is a very specific symptom which can be assessed objectively and is not a synonym of post-exertional “malaise”. Other authors have also proposed an operational definition of ME [19–21], but this definition has two important shortcomings. The definition [19–21] requires a sudden onset. Although ME is often initiated by an infection [2], a gradual onset is also possible [1–4]. The operational definition proposed [19–21] also interprets muscle fatigability/post-exertional muscle weakness as post-exertional “malaise”, but as argued, (post-exertional) muscle weakness and “malaise” are two different concepts. The tentative definition described here deviates from the London criteria [32] on two crucial points. Exercise-induced fatigue, the first criterion of the London criteria, has never been described a distinctive feature of ME [1–3] in the literature, while on the other hand, muscle fatigability/long-lasting post-exertional muscle weakness, the hallmark feature of ME [1–4], is not required to meet the London criteria [32].
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The operational definition of ME also deviates from the definition proposed by Hyde [33], since the proposed operational definition only incorporates discriminative features of ME and not symptoms related to “variable involvement of cardiac and other systems” [3], and does not include “testable brain changes” [33] (which are not proven yet). 5. Conclusions ME is a specific neuromuscular disease [1–4] and is not equivalent to CFS [11] or “ME/CFS” [13]. ME was described in the literature from 1938 [6] until 1992 [4], after which CFS [11], a fatigue syndrome, pushed ME [1–4] to the background. To unravel the aetiology and pathophysiology and to develop effective therapies for of ME as described in the literature [1–4], it is essential to investigate patients with ME (and ME only). For that reason, an operational definition is indispensable. This article proposes an operational definition of ME, based on the last formal definitions of ME [3,4], and the symptoms observed in the epidemic and endemic cases of ME [1] and reported by a large group of patients with well-defined ME [3]. An discriminative operational definition of ME should consists of the four mandatory features (minimum criteria for the diagnosis ME [1–4]): 1. 2. 3. 4.
muscle fatigability/prolonged muscle weakness after trivial exertion; neurological disturbance, especially of cognitive, autonomic and sensory functions; fluctuation of symptoms (within and between ‘episodes’); and a prolonged relapsing course.
The first two criteria of this tentative definition of ME justify the qualification “neuromuscular disease”, with specific characteristic and discriminative symptoms. Muscle fatigability/post-exertional muscle weakness (criterion 1) should be assessed objectively. This article proposes three criteria to operationalize “neurological disturbance” (criterion 2): at least one symptom related to cognitive dysfunction or one unclassified neurological symptom, one symptom related to autonomic dysfunction, and two symptoms related to sensory dysfunction (listed in Table 3). Several neurological symptoms can be confirmed objectively by medical tests. The criteria “fluctuation of symptoms” (criterion 3) and a “prolonged relapsing course” (criterion 4) will largely depend on self-report. The notion “prolonged” is not operationalized in the literature. However, since an early diagnosis is crucial, future experiments (surveys) should make clear which minimum duration is applicable. Based on the (proposed) minimum criteria for ME [1–4]), which discriminate ME from CFS [11] and other disorders, future studies into the criteria for “neurological disturbance” and the frequency of optional symptoms can be conducted. Acknowledgments: This article is dedicated to Melvin Ramsay, Elisabeth Dowsett, Donald Acheson, Gordon Parish, and other renowned researchers who have dedicated their professional career to myalgic encephalomyelitis and patients suffering from ME. Conflicts of Interest: The author declares no conflict of interest.
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