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Hypothermia in Multiple Sclerosis: Beyond the Hypothalamus? A Case Report and Review of the Literature.

1. Introduction

Multiple Sclerosis (MS) is the most common demyelinating disease and the major cause of neurological disability among young adults, affecting at least 2.5 million persons worldwide [1].

The cause of MS is unknown, but strong evidence suggests it is an autoimmune disorder of the central nervous system (CNS) where a chronic inflammatory response develops against myelin autoantigens leading to demyelination, scarring, and neuronal loss [2]. The multifocal nature of the disease implies that it can occur anywhere within the white and grey matter of the brain and spinal cord; thus its symptomatology can markedly differ based on the localisation of the lesions [1].

Radiological detection of multiple plaques and areas of atrophy is suggestive of MS, but the clinical correlation is often weak, with the absence of such findings failing to explain some dysfunctions [3]. Clinical hypothermia, defined as a core body temperature below 35.0[degrees]C [4], is an example of a rare and puzzling manifestation associated with MS. Hypothalamic pathology is considered its main cause but has been radiologically identified in very few of such MS patients.

In this article, we report on an hypothermic MS patient and review the literature on this subject, focusing on exploring whether extrahypothalamic dysfunctions along the thermoregulatory network may contribute to the development of this complication.

2. Case Presentation

A 66-year-old lady with a 21-year history of clinically definite MS, currently in the Secondary Progressive MS (SP-MS) phase, was admitted to hospital 14 times within a two-year period. On 10 occasions this was due to unexplained symptoms such as fatigue, confusion, worsening mobility, and dysarthria associated with hypothermia and suspected urinary tract infections (UTIs) (see Table 1).

Before these admissions, the patient was clinically stable with an Expanded Disability Status Scale (EDSS) score of 6.5 and had been hospitalised only once in the previous eight years, for cellulitis in the legs. At the time, she was suffering from limb weakness (mostly in the legs), spasticity, severe fatigue, reduced hand dexterity, and blepharospasm, but no other comorbidity. She could walk for 20 metres with a supporting frame but was otherwise wheelchair dependent. Since 2005, she had been receiving Botulinum Toxin injections for lower limb spasticity and blepharospasm and was on a trial of low-dose Naltrexone. The patient was also suffering from chronic urinary retention and constipation, for which she was taking an osmotic laxative. She had established normocytic anaemia and mildly elevated liver enzymes.

After repeated admissions with hypothermia, she developed chronically low body temperature (T: 34.0-36.0[degrees]C) and by March 2015, she had become bed-bound for most of the day (EDSS = 8.5) and was practising intermittent self-catheterisation.

She was first found hypothermic in March 2013 after an admission for confusion (GCS 10/15), dysarthria, and reduced mobility (see Table 1). The patient had progressively deteriorated in the preceding weeks and had suffered two falls. On admission, her temperature was 34.6[degrees]C, but respiratory rate (RR), heart rate (HR), blood pressure (BP), and [O.sub.2] saturations were unremarkable. Of note, no shivering or cold sensations were mentioned. Blood tests showed leukopenia, mild hyponatraemia (131 mmol/l) with normal K+ levels (4.6mmol/l), and acutely elevated Liver Function Tests (LFTs) with particularly high aminotransferases. Clotting tests and spinal fluid analysis (lumbar puncture; LP) results were within normal ranges. Chest X-ray (CXR) and abdominal ultrasonography (USS) were unremarkable. Computerised tomography (CT) scan of the head showed no evidence of acute findings.

Magnetic resonance imaging (MRI) of the brain using a 3 Tesla (T) scanner was performed with and without contrast. No old brain scans were available for comparison; however bilateral, white-matter changes and generalised atrophy consistent with MS were reported. No hypothalamic involvement was detected and spinal MRI was not performed.

The cause of her symptoms was not identified and the patient was treated prophylactically for Sepsis of Unknown Origin (SUO) with IV tazocin for five days. She was reviewed by general medicine and neurology and a diagnosis of Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH) secretion with impaired temperature regulation secondary to MS was considered. Naltrexone was discontinued in consideration of her elevated liver enzymes. The patient gradually improved over the next three weeks and was transferred to rehabilitation services before being discharged in June with a care package.

In July 2013, she was rehospitalised because of symptoms of urinary incontinence, leg oedema, and cellulitis and was treated prophylactically for a Urinary Tract Infection (UTI) (see Table 1).

In October, she presented to the hospital with confusion, lethargy, dysarthria, worsening of movements, and decreased taste in her mouth and was found hypothermic a second time (T: 33.5[degrees]C) (see Table 1). Her blood results showed hyponatraemia (127 mmol/l), normokalaemia (4.4 mmol/l), decreased serum osmolality (269 mOsm/kg) with a urine osmolality of 368 mOsm/kg, and no evidence of extracellular space depletion. Her general status gradually improved while still hypothermic (T: 34.3[degrees]C) and after five days she was discharged. Regular monitoring of her electrolyte levels was arranged.

After the third hospitalisation with unexplained hypothermia, our patient was readmitted a fourth time in December with lethargy, dysarthria, and limb weakness (see Table 1). Once again she was found hypothermic (T: 33.0[degrees]C) and bradycardic. She was treated empirically for urosepsis with IV tazocin, which was then switched to nitrofurantoin as blood tests did not suggest an infectious cause. Thyroid function tests (TFTs), cortisol, Vitamin D, prolactin, parathyroid hormone (PTH), and Ca + levels were within range and a liver autoimmune screen was negative. A second brain MRI (1.5 T) showed heavy demyelinating disease burden, but no hypothalamic involvement and a likely incidental small frontal meningioma. She was discharged after two weeks, asymptomatic while still hypothermic (T: 34.0[degrees]C).

Between March 2014 and March 2015, our patient was hospitalised nine more times (see Table 1). Confusion, lethargy, fatigue, dysarthria, and motor weakness were the most common symptoms and associated hypothermia was registered on at least six admissions. Interestingly, on two occasions, she presented with relatively abnormal high temperatures (T: 37.4[degrees]C and T: 37.0[degrees]C).

UTI was considered the likely cause of her symptoms in six instances and antibiotics were prescribed. A three-day course of intravenous methylprednisolone was added once, with no apparent benefits and in most cases the patient recovered spontaneously. In the light of only two positive urinary samples, the absence of typical UTI symptoms, and a negative cystoscopy, urology recommended intermittent self-catheterisation due to increased residual urine volume.

Following admission in October 2014, a repeat brain MRI with contrast was performed at 1.5 T that demonstrated recent callosal involvement (see Figure 1). A spinal MRI (1.5 T) was also arranged and revealed diffuse, patchy, T2 hyperintense lesions involving the majority of the cervical cord and T9-10 with associated atrophy (see Figure 1). These findings were discussed at the neuroradiology multidisciplinary team meeting and considered consistent with spinal MS rather than neuromyelitis optica spectrum disorder (NMOSD). This was confirmed by serology tests for anti-aquaporin 4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, which were both negative.

3. Discussion

Our patient developed clinical hypothermia (T < 35[degrees]C) associated with SP-MS. In the literature, this has been reported for 23 other MS cases (16 females) (see Table 2).

Most patients experienced deteriorations in cognition and consciousness (confusion, lethargy, or even stupor and coma) often accompanied by dysarthria (slurred speech) and worsening motor symptoms associated with hypothermia. On admission, their temperature ranged from 29.0[degrees]C to 35.0[degrees]C (see Table 2). In over half of these cases hypothermia had occurred after >20 years since diagnosis and was associated with severe disability (see Table 2). At least 12 of these patients suffered from more than one of such episodes (see Table 2).

Our patient developed more numerous episodes of hypothermia, superimposed on a chronic hypothermic state, than patients in previous reports. Chronic hypothermia was defined by the authors of this article as sustained hypothermia, typically lasting months. This had been previously reported in 5 other MS patients (see Table 2). In another case, chronic temperature changes were milder (35.0-36.5[degrees]C); hence this did not match the clinical definition of hypothermia [14].

Most MS patients achieved full or partial recovery after the first admission with hypothermia (see Table 2). Two deaths were associated with the initial episode [7, 12] and other two with subsequent ones [15, 17]. Transient haematological abnormalities were recorded in 16 patients during their first episode. Most commonly, these included thrombocytopenia and anaemia (see Table 2). Our anaemic patient, however, did not experience fluctuations of haematological parameters during admissions.

Previous cases of transiently deranged LFTs in hypothermic MS patients have been reported (see Table 2). In our case, mild, chronic LFT abnormalities could have been caused by Naltrexone-induced hepatic damage. Hyponatraemia was also reported in 5 of the previous cases (see Table 2). Cerebral salt wasting syndrome (CSW) and Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH) both present with hyponatraemia and hyposmolality and while SIADH was suspected in this case, it was not formally confirmed. Irrespective of hypothermia, SIADH had been previously reported in MS and associated with the presence of periventricular and/or hypothalamic lesions [19, 20].

More controversial is the pathophysiology of hypothermia in MS, partly because of our limited understanding of thermoregulation. Recently, however, the anatomical basis of the thermoregulatory pathways has been further characterised, mostly in rodents, which share strong similarities on thermal reflexes with humans [5]. An understanding of the current model is helpful to elucidate the importance of different areas in thermoregulation (see Figure 2).

Most of the reports on hypothermic MS patients describe deficits along the thermoregulatory circuit described (see Figure 2). For instance, our patient mentioned to be "feeling cold" only twice and, in the other 23 cases, this symptom is rarely mentioned, suggesting an impairment of the afferent tracts. Similarly, shivering and sympathetic activation (leading to CVC, BAT, and an increase in RR, HR, and BP) are considered physiological responses to mild hypothermia (32-35[degrees]C) [4] which were absent in our patient. In one of the early reports, two MS patients suffering from hypothermia were placed in a climatic chamber with a paraplegic pathological control subject [8]. They were exposed, in sequence, to environmental air temperatures of 27.0, 15.0, and 35.0[degrees]C for periods of 30-50 minutes [8]. Upon cold exposure, MS patients demonstrated cold awareness but impaired shivering and cutaneous vasoconstriction (CVC) and a small increase in the metabolic rate which resulted in a fall in core body temperature [8]. In the same conditions, the paraplegic control subject showed marked shivering and peripheral CVC, a more significant metabolic increase, and maintained core body temperature, as would be expected normally [8]. While no formal autonomic tests were arranged in our patient, no significant alterations of respiratory rate or heart rate were detected clinically or recorded in the observation charts.

Given that the hypothalamus is considered a key centre for thermoregulation, the focus of previous reports on hypothermia in MS was often on identifying hypothalamic lesions. In this case, a 3 T MRI and, subsequently, two 1.5 T MRI scans with contrast failed to detect hypothalamic involvement. Brain MRI was recorded in 15 other hypothermic MS patients, but radiological evidence for hypothalamic involvement was poor (n = 2; 13%) and in both cases it involved the preoptic area (POA) [17,18]. Out of three brains which were examined postmortem, hypothalamic pathology was evident in two [9, 12, 14] (see Table 2). Previous to autopsy, brain MRI had been performed in one of such cases but had failed to detect hypothalamic changes, despite identifying periventricular lesions [14]. Independently, an MRI study on 105 Caucasian patients, with clinically definite MS without hypothermia and typical lesions, revealed a similar (13%) frequency of radiologically-detectable hypothalamic changes, using a 1.5 Tesla MRI scanner, with conventional protocols [21]. Instead, a postmortem study on 17 nonhypothermic MS patients found hypothalamic lesions in 16 brains (97%), 60% ofwhich showed active inflammation [22]. Different factors may explain this disparity in results. Firstly, poor radiological sensitivity, particularly in the earlier reports on hypothermia in MS, may account for the low presence of hypothalamic lesions. Secondly, the patient cohorts of Qiu et al. [21] and Huitinga et al. [22] were different, with the latter having a greater mean age of disease duration which was statistically associated with a greater number of active hypothalamic lesions [22]. Although, using the current MR technology, we are unable to exclude very small hypothalamic lesions, we are mindful that the latter have not been found in other reported cases [14] and by contrast, they can be present in MS patients not affected by hypothermia.

Together with hypothalamic changes, callosal, brainstem, and spinal cord lesions were also detected at autopsy in hypothermic MS patients (see Table 2). All these areas have been previously associated with the development of hypothermic episodes and both the brainstem and the upper spinal cord are known as important thermoregulatory centres [4, 5, 14] (see Figure 2).

Brain callosal involvement, for instance, was detected in our case (see Figure 1) and in other four hypothermic MS patients via MRI or autopsy (see Table 2). In one instance, this was associated with hypothalamic disease [18]. In another report, MRI hyperintensities in the right posterior thalamus were associated with generalised atrophy, displaying clinical similarities to Shapiro's syndrome [16]. This is characterised by the congenital agenesis of the corpus callosum, hyperhidrosis, and recurrent hypothermia [23].

Brainstem lesions were associated with hypothermia in two other MS cases [4, 14]. In addition, a mesodiencephalic haematoma has been reported to be associated with hypothermia in a non-MS patient [24].

Upper spinal cord pathology in MS could also be associated with hypothermia. Spinal involvement of the cervical region is particularly common in MS and involves both white and grey matter, interneurons and motoneurons [25, 26]. Similarly to brainstem lesions, upper spinal cord changes could impair both ascending and descending tracts of the thermoregulatory circuit (see Figure 2). Extensive spinal cord lesions associated with brain and hypothalamic involvement were found at autopsy in one MS patient [12] and were radiologically detected in ours (see Figure 1). In the previously reported cases, however, spinal MRI was never reported and in ours it was only performed once, after repeated episodes of hypothermia. Hence, our ability to directly estimate the impact of spinal lesions on the development of hypothermia in MS is limited.

Given the prominent spinal involvement, the differential diagnosis of neuromyelitis optica spectrum disorder (NMOSD) was discussed at a neuroradiology meeting but was ruled out on the basis of clinical presentation, radiological features (multiple, confluent patchy lesions rather than longitudinally extensive lesions), and serology results (anti-AQP4 and anti-MOG antibody negative) [27].

Of note, hypothermia with autonomic impairment is commonly observed after upper Spinal Cord Injury (SCI) [28,29]. A retrospective study of 50 tetraplegic patients found that subnormal core body temperatures (35.0-36.4[degrees]C) were present in all patients and clinical hypothermia was recorded in 15 [30]. Similarities between dysfunctional sympathetic sudomotor skin responses were also identified among patients with transection of the SC at different levels and MS patients [31]. In spite of these resemblances and the frequent involvement of the spinal cord in MS, spinal lesions have not been reported to cause hypothermia in MS. This may be because, similarly to other lesions, a critical impairment of conduction is required before symptoms become manifest and in MS, unlike after SCI, this process is progressive and difficult to monitor.

Interestingly, our patient developed two episodes of abnormally high temperatures (above 36.5[degrees]C), associated with admissions (see Table 1). A clinical decay at high temperatures has been previously documented in MS patients ("Uhthoff's phenomenon") but, to our knowledge, was never reported to cause admissions in hypothermic individuals. This effect likely stems from decreased axonal conduction in damaged nerves at higher temperatures [32, 33]. Why this phenomenon occurs at lower temperatures in chronically hypothermic MS patients is controversial. This may indicate a more severe axonal damage or simply the resetting of the body thermostat at a new lower point where these higher temperatures are considered extreme [4,17].

Regardless of the causative mechanisms, no effective strategies have been devised to treat and prevent the development of hypothermic episodes in MS patients. Antibiotic treatment, in the absence of signs of infection, did not show any objective benefit for our patient and is known to promote antimicrobial resistance. Spontaneous recovery was commonly reported [18]. Treatment with steroids was shown to be potentially beneficial [17] but in our experience did not lead to substantial improvements. Our patient used an electrical blanket to control her body temperature at home, but the usefulness of this measure has not been systematically assessed. However, its use seems logical to prevent hypothermia since the neurological impairments along the thermoregulatory circuit.

4. Conclusion

In summary, hypothermia in MS patients remains a poorly understood phenomenon. The anatomical location of the causative lesions remains controversial and, based on the available evidence [4-6], we hypothesise that upper spinal cord, as well as brain stem lesions, may be involved in its pathogenesis in MS, independently of hypothalamic pathology. Given the disseminated nature of the disease, multiple, anatomically distinguished lesions, as opposed to a large single lesion, may also contribute to the development of this advanced complication by disrupting the thermoregulatory network at different levels [18]. In our opinion, in hypothermic MS patients, spinal MRI should be added to brain MRI to verify the presence of spinal involvement, due to its clinical importance. With the development of more sensitive neuroimaging and follow-up scans, anticipating the clinical course of hypothermia in these patients may be possible. Currently, in fact, the development of chronic hypothermia remains unpredictable.


Written informed consent was obtained from this patient for publication of this case report and all relevant material.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this article.


In loving memory of our patient, who passed away at Nottingham University Hospitals on 15 December 2017, the authors wish to thank her and her family for their support and encouragement.


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Francesco Berti (iD), (1) Zeeshan Arif (iD), (1) Cris Constantinescu (iD), (1,2) and Bruno Gran (iD), (2)

(1) Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham, UK

(2) Department of Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK

Correspondence should be addressed to Bruno Gran;

Received 18 August 2017; Revised 6 January 2018; Accepted 6 February 2018; Published 21 March 2018

Academic Editor: Isabella Laura Simone

Caption: Figure 1: Brain and spinal MRI of the patient following admission on 12 October 2014. (a) Brain T2W axial MRI (1.5 T) demonstrating the characteristic periventricular lesions of MS. (b) Magnification of brain FLAIR sagittal MRI showing involvement of the corpus callosum. (c) Sagittal T2W spinal MRI of the cervical cord with diffuse, patchy lesions. T2W: T-2 weighted; FLAIR: Fluid-Attenuated Inversion Recovery; T: Tesla.

Caption: Figure 2: A schematic view of the main components of the thermoregulatory pathway according to the current main model [5, 6]. It is thought that cool and warm-sensitive cutaneous thermoreceptors detect changes in skin temperature. These are relayed via parallel ascending spinal cords tracts, to the pontine lateral parabrachial nucleus (LPB) [5]. In turn, the LPB transmits these to the anterior hypothalamus [5]. Afferent information is also separately sent to the cortex (thalamocortical tract) [5]. The hypothalamus integrates these signals with sensory information from other areas like visceral thermoreceptors and osmoreceptors to generate an effector response. In physiological conditions, after an increase in cutaneous cool signals is detected by the hypothalamic median preoptic subnucleus (MnPO) of the Preoptic Area (POA), disinhibition of the efferent pathways (in red color) leads to the activation of the three main heat- maintenance/producing mechanisms [5]. The rostral ventromedial medulla, including the rostral raphe pallidus nucleus (rRPa), is considered a key supraspinal area which regulates cutaneous vasoconstriction (CVC) and brown adipose tissue (BAT) thermogenesis (sympathetic (in green color)) and shivering thermogenesis (somatic (in orange color)) [5, 6].
Table 1: Summary of patient admissions to hospital between March 2013
and March 2015.

Admission           Main        at admission   New finding(s)
date            complaint(s)    [degrees]C)

24 March         Confusion,         34.6         GCS (10/15)
2013             dysarthria,                     Leukopaenia
                   reduced                      Hyponatraemia
                  mobility,                    (Na+ 131 mmol/
                 and recent                      l), mildly
                    falls                       deranged LFTs
                                               Normal LP, CXR,
                                                and abdominal

18 July 2013       Urinary          35.8             No
                 oedema, and

                  Confusion                       Nystagmus
18 October        lethargy,         33.5          Diplopia
2013             dysarthria,                   Decreased limb
                  worsening                         power
                 movements,                     Hyponatraemia
                     and                        (127 mmol/l),
                  decreased                     normokalaemia
                    taste                       (4.4 mmol/l)
                                               osmolality: 269
                                               mOsm/kg; Urine
                                               Osmolality: 368

7 November      Dizziness on        33.0             No
2013              standing

31 December       Lethargy,         33.0        Bradycardia,
2013               unwell,                      normal liver
                 dysarthria,                     autoimmune
                  and limb                     screen, Vitamin
                  weakness                        D, TFTs,
                                               prolactin, PTH,
                                                calcium, and
                                               random cortisol

16 March 2014      Feeling          32.8       RUQ tenderness
                    cold,                       Murphy's +ve.
                 unwell, and                   Abdominal USS:
                 dysarthria                    cholelithiasis
                                               and contracted
                                                gall bladder

22 May 2014       Weakness          33.1        Positive MSU,
                                                   CRP 41

27 May 2014     Feeling cold        33.7             No
                and weakness

15 September     Right flank        32.7         Urinalysis
2014                pain                        (positive for
                                               leukocites and
                                                 blood +++)

2 October        Right flank        34.0             No
2014                pain,

12 October       Dysarthria,         NK        Hyponatraemia,
2014              fatigue,                      hyperkalaemia
                 confusion,                    (Na+ 125 mmol/
                  weakness,                    l, K+ 5.8 mmol/
                     and                        l), eGFR 59,
                  decreased                    urea 8.4 mmol/
                    power                      l MSU (positive
                                               for leukocytes)
                                                Mixed growth,

24 October       Neck pain,         37.4             No
2014            fatigue, and

23 March          Lethargy          31.0             No

25 March        Lethargy and        37.0          Dysmetric
2015                high-                         saccades.
                 temperature                     Cerebellar
                                               Worsening power
                                               with bilateral
                                               upgoing plantar
                                               Bilateral lower
                                                 leg oedema.

Admission       Confirmed     Treatment(s)        Disease
date            diagnosis                          course

24 March         No ?SUO     IV antibiotics,     Discharged
2013              ?SIADH       naltrexone        in 3 weeks
                              discontinued       (homeother-
                             because of LFTs      mic) with
                                                 package and

18 July 2013     No ?UTI       Antibiotics       Discharged

18 October      No ?SIADH      Supportive       Discharged in
2013                                            5 days while

7 November          No         Supportive        Discharged

31 December      No ?UTI       Antibiotics     Discharged in 2
2013                                              weeks (T:

16 March 2014       No         Antibiotics      Discharged in
                             then supportive       2 weeks

22 May 2014        UTI         Antibiotics     Discharged the
                                                  next day

27 May 2014         No         Supportive      Discharged in 3

15 September       UTI         Antibiotics     Discharged in a
2014                                                week

2 October        AKI and       Antibiotics     Discharged in 6
2014               ?UTI                             days

12 October         UTI        Antibiotics 3    Discharged in 2
2014                           days of IV           weeks

24 October       No ?UTI       Antibiotics           NK

23 March         No? UTI       Supportive       Discharged on
2015                                              same day

25 March            No         Supportive       Discharged 2
2015                                             days later

Admission          Neuroimaging

24 March        Head CT and brain
2013              MRI. No acute
                Bilateral, white-
                matter changes and
                   atrophy. No

18 July 2013            No

18 October              No

7 November              No

31 December       Brain MRI: no
2013             acute findings.
                disease burden and
                     a likely
                 incidental small
                  meningioma. No

16 March 2014           No

22 May 2014             No

27 May 2014             No

15 September            No

2 October               No

12 October       Brain and spinal
2014              MRI Extensive
                   lesions with
                evidence of recent
                  Spinal imaging
                revealed diffuse,
                    patchy, T2
                lesions involving
                 the majority of
                the cervical cord
                  and T9-10 with
                associated atrophy

24 October              No

23 March                No

25 March                No

Not known (NK); Glasgow Coma Scale (GCS); acute kidney injury (AKI);
mid-stream urine (MSU); C-reactive protein (CRP); right upper quadrant
(RUQ); sepsis of unknown origin (SUO); liver function tests (LFTs);
lumbar puncture (LP); chest X-ray (CXR); ultrasonography (USS);
thyroid function tests (TFTs); parathyroid hormone (PTH); estimated
glomerular filtration rate (eGFR); Syndrome of Inappropriate Anti-
Diuretic Hormone (SIADH).

Table 2: Review of the literature: summary of the 1st presentation of
patients with hypothermia in Multiple Sclerosis (MS) and the clinical
course of the disease.

                         duration;          Main           Temperature
              Patient    MS-type;        complaint(s)      at admission
References    details      EDSS        before admission    ([degrees]C)

[7]            61 F        NK;            Lethargy             29.4
                           NK;            anorexia,
                            NK        poor fluid intake

[8]            41 F      7 years;          3 weeks             32.6
                           NK;           confusion,
                         EDSS: 7.0          apathy

[8]            52 F     24 years;         3 weeks:             31.0
                           NK;           confusion,
                         EDSS: 8.0         lethargy

[9]            55 F     24 years;          1 week:             33.0
                           NK;           confusion,
                         EDSS: 6.0        lethargy

[9]            55 F     22 years;          4 week:
                           NK;           confusion,             NK
                            NK          bradyphrenia,

[9]            58 M     16 years;         2 weeks:             <35
                           NK;            lethargy,
                         EDSS: 7.0       dysarthria,

[10]           52 M      14 years;        Augmented            32.8
                           NK;          motor deficits

[11]           63 F     25 years;          Visual              32.4
                           NK;          disturbances,
                            NK           depression
                                      paranoid, unable
                                         to stand up
                                         without help

[11]           68 F     32 years;         3 weeks:             31.6
                           NK;              gait
                            NK         abnormalities,

[12]           53 F         NK;       5 days: lethargy         29.0
                           NK;           dysphagia,
                            NK            dysarthria

                         10 years;        Few days:
[13]           44 F       PR-MS;         confusion,            33.3
                            NK         disorientation,

                                           3 weeks:
[14]           48 M      5 years;        confusion,         Initially
                           NK;         disorientation,      36.0 then
                         EDSS: 6.0       dysarthria            31.0
                                          cold lower

[14]           59 M     30 years;         4 weeks:             33.0
                           NK;           increasing
                         EDSS: 7.0    fatigue, lethargy,
                                       confusion, then
                                       dysphagia, and

[14]           57 F     20 years;         Decreased            35.0
                           NK;            mobility,
                         EDSS: 7.0        lethargy,

[14]           64 F     30 years;     Deterioration of         34.7
                           NK;         motor function,
                         EDSS: 9.0         speech

[14]           47 F     No previous    Withdrawal and          29.0
                            MS             lethargy
                         in retro-
                         EDSS: 3.0

[15]           NK F         NK;           Motor and             NK
                            NK;       cognitive decline

[15]           NK F         NK;           Motor and             NK
                            NK;       cognitive decline

[16]           45 F     28 years;         4 weeks:             33.4
                         SP- MS;         hypothermia
                         EDSS: 8.0    (32-33[degrees]C),
                                      and hypoglycaemia

[4]             61F      30 years;       Confusion,            33.9
                          SP-MS;          agitation

                                       3 weeks: slurred
[17]            41M      7 years;        dysarthria,           30.0
                            NK;            paranoid
                            NK            delusions,
                                      auditory, visual
                                         and tactile

                                          Few weeks:
[18]           39 M     24 years;         augmented            31.0
                          SP-MS;         spasticity,
                         EDSS: 6.5        cognitive

[18]           49 M     32 years;         Confusion            32.4
                         EDSS: 7.5

               Cognitive     New neurological      Dysarthria
              symptoms at        signs and           and/or
References     admission         symptoms          dysphagia

[7]               NK                NK                 NK

[8]           Confusion,     Marked rigidity           No
                Stupor         in all limbs

[8]              Coma               No                 No

[9]            Confusion       Generalised             No
                              neck stiffness

[9]               NK            Augmented              No

[9]             Memory        Tetraparesis,        Dysarthria
                deficit      bilateral central       and/or
                                 nystagmus         dysphagia

[10]           Confusion     Augmented motor           No

[11]           Confusion        Worsening          Dysarthria
                             signs: bilateral
                              Babinski sign,
                             paresthesia, and
                              ataxia in the
                               right arm and
                              mild postural

[11]          Confusion,          Severe           Dysarthria
              drowsiness       paraparesis,
                              Babinski sign,
                              partial right
                              lateral rectus
                             palsy, cerebellar

[12]           Confusion         Spastic           Dysarthria
                             tetraparesis with
                            bilateral extensor
                               plantar but
                             depressed eflexes

                            Flaccid paraplegia
[13]           Confusion      and cerebellar           No
                              syndrome (not

                            Initially flaccid
                             paraparesis and
                            increased tone in
                             the upper limbs.
[14]            Stupor      Deterioration over     Dysarthria
                            48 h. He developed
                            repetitive facial
                             twitching, neck
                             stiffness, left
                            lower motor facial
                              weakness, and

[14]            Stupor              NK            Dysphagia,

[14]           Oriented      Bilateral optic      Dysarthria,
              (initially)   atrophy and absent     dysphagia
                              response, neck
                             rigidity, spastic

[14]           Confusion       Periorbital         Dysarthria
                             oedema, augmented
                             impaired palatal

[14]             Coma        Neck stiffness,           NK
                            hypertonia. After
                            3 days: bilateral
                             extensor plantar
                             responses, mild
                            paraparesis, optic
                                disc pallor

[15]          Drowsiness    Augmented flaccid      Dysarthria

[15]          Drowsiness    Augmented flaccid      Dysarthria

[16]            Stupor              No             Dysarthria

[4]           Confusion,            No                 No

                             Bilateral facial
                              droop, miosis,
[17]          Confusion      paraplegia (also      Dysarthria
               then coma     present before),
                               and bilateral
                            upper extremities

[18]            Stupor           Spastic          Dysarthria,
                               tetraparesis        dysphagia

[18]          Psychomotor       Augmented         Dysarthria,
                slowing       tetraparesis,        dysphagia
                            bilateral pyramidal
                             syndrome, right
                            cerebellar syndrome

                 Haematological       and plasma/    Neuroimaging and/
               abnormalities and        urinary         or autopsy
References           onset           osmolalities         studies

[7]           Hb 12.9 g/dl; MCV 84        NK                No
               fl Platelets 19 x
               [10.sup.9]/l Bone
                marrow aspirate:
              erythroid hypoplasia

[8]           After 1/52: Anaemia         No            Head CT: no
                 (Hb 7.9 g/dl)                          abnormality
              Thrombocytopenia (61                       detected
                x [10.sup.9]/l)

              Thrombocytopenia (50
[8]            x [10.sup.9]/l) at    Yes: (Na+ 107          No
               admission, peaking       mmol/l)
               after 5 days (28 x      (?SIADH)
               [10.sup.9]/l) and
               anaemia (Hb 7.4 g/

                                                        Head CT: no
[9]              8 days after:            No            abnormality
              pancytopenia Hb 9.2                     detected Brain
              g/dl, Platelet 80 x                    autopsy multiple
                 [10.sup.9]/l,                        old plaques at
                Leukocytes 2.9 x                     various locations
                  [10.sup.9]/l                         (incl. basal
               hypothermia. Brain                     ganglia, corpus
                    MRI and                              callosum,
                                                      occipital white
                                                     matter, and right
                                                     upper cerebellar
                                                       peduncle). No
                                                      lesions except
                                                     some recent axon
                                                       swellings and
                                                         cell loss

                                                     Brain MRI and CT
                                                      performed after
[9]                    No                 No         the 2nd admission
                                                     with hypothermia.
                                                       Brain MRI and
                                                         head CT:
                                                     Important lesions
                                                       and posterior
                                                      part of corpus
                                                        callosum No

[9]            Thrombocytopenia:          No             Brain MRI
               100 x [10.sup.9]/l                     performed after
                                                     the 4th admission
                                                     with hypothermia.
                                                        Brain MRI:
                                                        plaques. No

[10]                   No            Yes: (Na+ 114     Brain MRI: No
                                        mEq/1),        hypothalamic
                                        plasma            lesions
                                       (? SIADH)

[11]           Deranged LFTs (ALT         No            Brain MRI:
                 and AST mildly                        diffuse white
                  raised with                        matter lesions No
               hypoalbuminaemia,                       hypothalamic
                   31.7 g/1)                              lesions

[11]                 Severe               No            Brain MRI:
                hypoalbuminaemia                         multiple
                  (18.9 g/1),                         periventricular
              decreased folic acid                      lesions. No

                                                      Brain and spine
[12]           Thrombocytopenia:          No.        autopsy: multiple
                 platelets 79 x                       plaques in the
                  [10.sup.9]/l                       brain and spinal
              Increased APTT ?DIC                      cord. A large
                 Raised amylase                        hypothalamic
                   (321IU/1)                         plaque was found
                                                     pancreatitis, and
                                                     died evidence of
                                                     current activity
                                                     and demyelination

                                                      Brain MRI: T2W
[13]                   No                 No         hyperintensities
                                                          in the
                                                       white matter

                                                     CT head: moderate
                                                      brain atrophy.
                                                     Previous MRIs had
                                                       been normal.
                                                     Brain MRI: after
                                                        1st and 2nd
                                                      admissions with
                                                       multiple high
[14]          Thrombocytopenia: 27        No            signals in
                 x [10.sup.9]/l                       periventricular
              Anaemia: Hb 12.7 g/                    white matter. No
              dl. Increased PT and                     hypothalamic
              APTT and low folate                     lesions. Brain
                                                      autopsy plaques
                                                      midbrain, pons,
                                                        medulla and
                                                     (incl. posterior

[14]          Thrombocytopenia 95         No                NK
                 x [10.sup.9]/l

[14]           Thrombocytopenia,     Yes: (Na+ 130       Head CT:
               when normothermic        mmol/1)          bilateral
                (141) then 99 x                       periventricular
              [10.sup.9]/l. Raised                      low density
               APTT time. Raised                          lesions
              platelets antibodies

[14]                   No            Yes: (Na+ 130          NK
                                      with fluid
                                     Normal plasma
                                      and urinary

[14]           Thrombocytopenia:          No            Brain MRI:
               33 x [10.sup.9]/l                     diffuse cortical
                Anemia: Hb 10.2                        atrophy, T2W
                                                        lesions. No

[15]            Thrombocytopenia          NK         Head CT and brain
                                                          MRI: No

                                                     Head CT and brain
[15]            Thrombocytopenia          NK              MRI: No

[16]          Chronic normocytic       Yes: (124     Head CT and brain
               anaemia. Elevated     mmol/l). ?CSW   MRI: known right
              APTT (61 s). Raised      syndrome       parietal defect
               CRP with negative                      (previous brain
                blood cultures.                          abscess),
                 Hypoglycaemia                          generalised
                                                       white matter
                                                      particularly in
                                                     the callosum and
                                                      a hyperintense
                                                       lesion in the
                                                     septal region of
                                                      right thalamus.
                                                      No hypothalamic

[4]                    No                 No             Brain MRI
                                                      performed after
                                                      3rd hypothermic
                                                      and brain stem
                                                     plaques were seen
                                                        with small
                                                     vessel ischaemia
                                                     in the ganglionic
                                                        regions. No

                                                        Brain MRI:
                                                     increased overall
[17]              Platelets:              No          lesions and new
               113000/[mm.sup.3]                     T2W hypothalamic

                                                      Brain MRI: T2W
                                                      multiple white
                                                      matter lesions
                Thrombocytopenia                      and atrophy of
[18]          (75 x [10.sup.9]/l)         No         corpus callosum.
               Leukopenia (0.7 x                       Hypothalamic
                 [10.sup.9]/l)                         involvement
              Elevated APTT (37 s)                    with bilateral
               Raised ALT and AST                      nonenhancing
                                                      lesions. After
                                                        1 year MRI
                                                         showed no
                                                       longer signs

[18]            Thrombocytopenia          No          Brain MRI: T2W
              (79 x [10.sup.9]/l)                      white matter
               Raised AST and ALT                       lesions. No

                                      Type of
                                  hypothermia and
                  Suspected         (number of
                diagnosis and       hypothermic
References     disease course        episodes)

[7]                 Death            Acute (1)

[8]             Treated with       Chronic: (1)
               rewarming. Full
              clinical recovery
                  in 6 days

                Treated with
[8]           steroids, passive    Chronic: (1)
                 saline, and
              furosemide. Full
              clinical recovery
                  in 5 days

[9]               Developed         Acute: (4)
                Treated with
              antibiotics. Full
              clinical recovery

[9]               Developed
              bronchopneumonia.     Acute: (2)
                Treated with
               antibiotic and
               rewarming. Full

[9]               Developed         Acute: (4)
                Treated with
               antibiotics and
              passive rewarming
                recovered in
              days. Some motor

               Treatment with
[10]          NaCl infusion and     Acute: (3)
              Hypothermia self-
                Clinical full

[11]            Treated with         Acute (1)
              passive rewarming
               and parenteral
                 thiamine (?
              Normothermia in 3

[11]            Treated with         Acute (1)
                 thiamine (?
                Full recovery
               within 1 month

[12]             rewarming,          Acute (1)
              antibiotics, and
              pancreatitis, and

              Passive rewarming
[13]          and full clinical         NK
               recovery within
                   10 days

              Initially treated
               with IV methyl-
              prednisolone for
              MS relapse, then
              with antibiotics
               for ?UTI. Then,
[14]           after furher 48      Acute then
               h. Packed cells     chronic: (2)
               platelets, and
               plasma proteins
               transfusion for
              Discharged in 30
               days. Residual
               mild upper limb
                weakness, and
               sensory dificit
                  after T12

[14]          Passive rewarming      Acute (2)
               and IV fluids.
               Normothermia in
                  36 hours.
                psychosis and
              confusion, MI and
                 severe LVF.

[14]            Rewarming, IV       Acute: (2)
                fluids and IV
                nisolone and
               antibiotics for
                  ?UTI and
               infections were
              within 24 hours.
                Full clinical
                recovery in 4

[14]               Passive           Acute (1)
               Normothermia in
               24 hours. Full
              clinical recovery
                  in 7 days

[14]             Rewarming.         Acute: (2)
              Normothermia in 3
               days. Residual
                physical and

[15]                 NK            Chronic with
                                  acute episode:

                                   Chronic with
[15]                 NK               acute
                                   episodes (NK)

[16]           Antibiotics, IV      Acute: (6)
              fluids. Initially
               recovered then
                within a week
              stupor and severe
              Within 2 weeks a
               3rd episode of
              bradycardia, and
              hypotension. She
              was treated with
                droxidopa and
               then discharged
              once normothermic
                 and stable

[4]                                Chronic with
                                   acute episodes
                 Spontaneous            (6)
               improvement and
              discharge with a
                  T of 35.2

               rewarming. Then
               antibiotics and
[17]           assistance for        Acute (6)
                 ?SUO. Full
              clinical recovery
              in 6 weeks. Five
                 monthly IV
               infusions (1 g/

[18]           Full clinical            NK

[18]           Antibiotics for       Acute (1)
                sepsis and 3
                Full clinical
               recovery within

Expanded Disability Status Scale (EDSS); Primary Progressive MS (PP-
MS); Secondary Progressive MS (SP-MS); not known (NK); aspartate
transaminase (AST); alanine transaminase (ALT); disseminated
intravascular coagulation (DIC); activated partial thromboplastin time
(APTT); Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH); mean
corpuscular volume (MCV); T-2 weighted (T2W).
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Title Annotation:Case Report
Author:Berti, Francesco; Arif, Zeeshan; Constantinescu, Cris; Gran, Bruno
Publication:Case Reports in Neurological Medicine
Date:Jan 1, 2018
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