Hypothermia in Multiple Sclerosis: Beyond the Hypothalamus? A Case Report and Review of the Literature.
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 .
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 . 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 .
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 . Clinical hypothermia, defined as a core body temperature below 35.0[degrees]C , 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.
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 .
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 . 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)  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 . 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 . 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 . 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 . 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 . 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 . Instead, a postmortem study on 17 nonhypothermic MS patients found hypothalamic lesions in 16 brains (97%), 60% ofwhich showed active inflammation . 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.  and Huitinga et al.  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 . 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  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 . In another report, MRI hyperintensities in the right posterior thalamus were associated with generalised atrophy, displaying clinical similarities to Shapiro's syndrome . This is characterised by the congenital agenesis of the corpus callosum, hyperhidrosis, and recurrent hypothermia .
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 .
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  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) .
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 . Similarities between dysfunctional sympathetic sudomotor skin responses were also identified among patients with transection of the SC at different levels and MS patients . 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 . Treatment with steroids was shown to be potentially beneficial  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.
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 . 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; firstname.lastname@example.org
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) . In turn, the LPB transmits these to the anterior hypothalamus . Afferent information is also separately sent to the cortex (thalamocortical tract) . 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 . 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. Temperature 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 USS 18 July 2013 Urinary 35.8 No incontinence, oedema, and cellulitis 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) Hyposmolarity (serum osmolality: 269 mOsm/kg; Urine Osmolality: 368 mOsm/kg) 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, urinary incontinence, confusion, and persistently low temperatures 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, possible contamination 24 October Neck pain, 37.4 No 2014 fatigue, and weakness 23 March Lethargy 31.0 No 2015 25 March Lethargy and 37.0 Dysmetric 2015 high- saccades. temperature Cerebellar signs. Worsening power with bilateral upgoing plantar reflexes. 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 care package and rehabilitation 18 July 2013 No ?UTI Antibiotics Discharged 18 October No ?SIADH Supportive Discharged in 2013 5 days while still hypothermic (T: 34.3[degrees]C) 7 November No Supportive Discharged 2013 31 December No ?UTI Antibiotics Discharged in 2 2013 weeks (T: 34.0[degrees]C) 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 days 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 steroids 24 October No ?UTI Antibiotics NK 2014 23 March No? UTI Supportive Discharged on 2015 same day 25 March No Supportive Discharged 2 2015 days later Admission Neuroimaging date 24 March Head CT and brain 2013 MRI. No acute findings. Bilateral, white- matter changes and generalised atrophy. No hypothalamic involvement 18 July 2013 No 18 October No 2013 7 November No 2013 31 December Brain MRI: no 2013 acute findings. Heavy demyelinating disease burden and a likely incidental small frontal meningioma. No hypothalamic involvement 16 March 2014 No 22 May 2014 No 27 May 2014 No 15 September No 2014 2 October No 2014 12 October Brain and spinal 2014 MRI Extensive demyelinating lesions with evidence of recent callosal involvement. Spinal imaging revealed diffuse, patchy, T2 hyperintense lesions involving the majority of the cervical cord and T9-10 with associated atrophy 24 October No 2014 23 March No 2015 25 March No 2015 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. Disease duration; Main Temperature Patient MS-type; complaint(s) at admission References details EDSS before admission ([degrees]C)  61 F NK; Lethargy 29.4 NK; anorexia, NK poor fluid intake  41 F 7 years; 3 weeks 32.6 NK; confusion, EDSS: 7.0 apathy  52 F 24 years; 3 weeks: 31.0 NK; confusion, EDSS: 8.0 lethargy  55 F 24 years; 1 week: 33.0 NK; confusion, EDSS: 6.0 lethargy visual hallucinations  55 F 22 years; 4 week: NK; confusion, NK NK bradyphrenia, incontinence  58 M 16 years; 2 weeks: <35 NK; lethargy, EDSS: 7.0 dysarthria, dysphagia  52 M 14 years; Augmented 32.8 NK; motor deficits NK  63 F 25 years; Visual 32.4 NK; disturbances, NK depression paranoid, unable to stand up without help  68 F 32 years; 3 weeks: 31.6 NK; gait NK abnormalities, dysarthria  53 F NK; 5 days: lethargy 29.0 NK; dysphagia, NK dysarthria 10 years; Few days:  44 F PR-MS; confusion, 33.3 NK disorientation, hallucinations 3 weeks:  48 M 5 years; confusion, Initially NK; disorientation, 36.0 then EDSS: 6.0 dysarthria 31.0 deteriorating mobility, drowsiness, cold lower extremities  59 M 30 years; 4 weeks: 33.0 NK; increasing EDSS: 7.0 fatigue, lethargy, confusion, then drowsiness, dysphagia, and dysarthria  57 F 20 years; Decreased 35.0 NK; mobility, EDSS: 7.0 lethargy, dysphagia,  64 F 30 years; Deterioration of 34.7 NK; motor function, EDSS: 9.0 speech disturbance, peripheral oedema, fluctuating consciousness  47 F No previous Withdrawal and 29.0 MS lethargy (diagnosed in retro- spective); EDSS: 3.0  NK F NK; Motor and NK NK; cognitive decline NK  NK F NK; Motor and NK NK; cognitive decline NK  45 F 28 years; 4 weeks: 33.4 SP- MS; hypothermia EDSS: 8.0 (32-33[degrees]C), stupor, hypotension, hyponatraemia, and hypoglycaemia  61F 30 years; Confusion, 33.9 SP-MS; agitation NK 3 weeks: slurred speech, hypothermia,  41M 7 years; dysarthria, 30.0 NK; paranoid NK delusions, auditory, visual and tactile hallucinations Few weeks:  39 M 24 years; augmented 31.0 SP-MS; spasticity, EDSS: 6.5 cognitive decline, confusion  49 M 32 years; Confusion 32.4 PP-MS; EDSS: 7.5 Cognitive New neurological Dysarthria symptoms at signs and and/or References admission symptoms dysphagia  NK NK NK  Confusion, Marked rigidity No Stupor in all limbs  Coma No No  Confusion Generalised No myoclonus neck stiffness  NK Augmented No paraparesis  Memory Tetraparesis, Dysarthria deficit bilateral central and/or nystagmus dysphagia  Confusion Augmented motor No paresis  Confusion Worsening Dysarthria neurological signs: bilateral Babinski sign, paraparesis, paresthesia, and ataxia in the right arm and mild postural tremor  Confusion, Severe Dysarthria drowsiness paraparesis, bilateral Babinski sign, asterixis, partial right lateral rectus palsy, cerebellar signs  Confusion Spastic Dysarthria tetraparesis with bilateral extensor plantar but depressed eflexes Flaccid paraplegia  Confusion and cerebellar No syndrome (not augmented) Initially flaccid paraparesis and increased tone in the upper limbs.  Stupor Deterioration over Dysarthria 48 h. He developed repetitive facial twitching, neck stiffness, left lower motor facial weakness, and decerebrate posturing  Stupor NK Dysphagia, dysarthria  Oriented Bilateral optic Dysarthria, (initially) atrophy and absent dysphagia oculocephalic response, neck stiffness, rigidity, spastic tetraparesis  Confusion Periorbital Dysarthria oedema, augmented tetraparesis, impaired palatal movements  Coma Neck stiffness, NK generalised hypertonia. After 3 days: bilateral extensor plantar responses, mild paraparesis, optic disc pallor  Drowsiness Augmented flaccid Dysarthria paresis  Drowsiness Augmented flaccid Dysarthria paresis  Stupor No Dysarthria  Confusion, No No agitation Bilateral facial droop, miosis,  Confusion paraplegia (also Dysarthria then coma present before), and bilateral upper extremities weakness  Stupor Spastic Dysarthria, tetraparesis dysphagia  Psychomotor Augmented Dysarthria, slowing tetraparesis, dysphagia bilateral pyramidal syndrome, right cerebellar syndrome Hyponatremia Haematological and plasma/ Neuroimaging and/ abnormalities and urinary or autopsy References onset osmolalities studies  Hb 12.9 g/dl; MCV 84 NK No fl Platelets 19 x [10.sup.9]/l Bone marrow aspirate: erythroid hypoplasia  After 1/52: Anaemia No Head CT: no (Hb 7.9 g/dl) abnormality Thrombocytopenia (61 detected x [10.sup.9]/l) Thrombocytopenia (50  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/ dl) Head CT: no  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 hypothalamic lesions except some recent axon swellings and cell loss Brain MRI and CT performed after  No No the 2nd admission with hypothermia. Brain MRI and head CT: Important lesions in periventricular and posterior part of corpus callosum No hypothalamic lesions  Thrombocytopenia: No Brain MRI 100 x [10.sup.9]/l performed after the 4th admission with hypothermia. Brain MRI: several periventricular plaques. No hypothalamic lesions  No Yes: (Na+ 114 Brain MRI: No mEq/1), hypothalamic plasma lesions hyposmolarity (? SIADH)  Deranged LFTs (ALT No Brain MRI: and AST mildly diffuse white raised with matter lesions No hypoalbuminaemia, hypothalamic 31.7 g/1) lesions  Severe No Brain MRI: hypoalbuminaemia multiple (18.9 g/1), periventricular decreased folic acid lesions. No hypothalamic lesions Brain and spine  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 with pancreatitis, and died evidence of current activity and demyelination Brain MRI: T2W  No No hyperintensities in the periventricular white matter CT head: moderate brain atrophy. Previous MRIs had been normal. Brain MRI: after 1st and 2nd admissions with hypothermia: multiple high  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 in periventricular, midbrain, pons, medulla and hypothalamus (incl. posterior hypothalamic nucleus)  Thrombocytopenia 95 No NK x [10.sup.9]/l  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  No Yes: (Na+ 130 NK mmol/1) corrected with fluid restriction. Normal plasma and urinary osmolalities  Thrombocytopenia: No Brain MRI: 33 x [10.sup.9]/l diffuse cortical Anemia: Hb 10.2 atrophy, T2W hyperintense periventricular lesions. No hypothalamic lesions  Thrombocytopenia NK Head CT and brain MRI: No hypothalamic lesions Head CT and brain  Thrombocytopenia NK MRI: No hypothalamic lesions  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 atrophy, periventricular white matter lesions, particularly in the callosum and a hyperintense lesion in the septal region of right thalamus. No hypothalamic lesions  No No Brain MRI performed after 3rd hypothermic episode. Periventricular and brain stem plaques were seen with small vessel ischaemia in the ganglionic regions. No hypothalamic involvement Brain MRI: increased overall  Platelets: No lesions and new 113000/[mm.sup.3] T2W hypothalamic hyperintensity Brain MRI: T2W multiple white matter lesions Thrombocytopenia and atrophy of  (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 preoptic lesions. After 1 year MRI showed no longer signs  Thrombocytopenia No Brain MRI: T2W (79 x [10.sup.9]/l) white matter Raised AST and ALT lesions. No hypothalamic involvement Type of hypothermia and Suspected (number of diagnosis and hypothermic References disease course episodes)  Death Acute (1)  Treated with Chronic: (1) passive rewarming. Full clinical recovery in 6 days Treated with  steroids, passive Chronic: (1) rewarming, hypertonic saline, and furosemide. Full clinical recovery in 5 days  Developed Acute: (4) bronchopneumonia. Treated with antibiotics. Full clinical recovery  Developed bronchopneumonia. Acute: (2) Treated with antibiotic and passive rewarming. Full clinical recovery.  Developed Acute: (4) bronchopneumonia. Treated with antibiotics and passive rewarming recovered in days. Some motor deterioration remained Treatment with  NaCl infusion and Acute: (3) fluid restrictions. Hypothermia self- resolved. Clinical full recovery  Treated with Acute (1) passive rewarming and parenteral thiamine (? Wernicke Encephalopathy) Normothermia in 3 weeks  Treated with Acute (1) parenteral thiamine (? Wernicke Encephalopathy). Full recovery within 1 month Passive  rewarming, Acute (1) antibiotics, and atropine. Development bronchopneumonia, pancreatitis, and died Passive rewarming  and full clinical NK recovery within 10 days Initially treated with IV methyl- prednisolone for MS relapse, then with antibiotics for ?UTI. Then, passive rewarming. Normothermia  after furher 48 Acute then h. Packed cells chronic: (2) platelets, and plasma proteins transfusion for bleeding. Discharged in 30 days. Residual spastic paraparesis incoordination, mild upper limb weakness, and sensory dificit after T12  Passive rewarming Acute (2) and IV fluids. Normothermia in 36 hours. Paranoid psychosis and confusion, MI and severe LVF. Residual cognitive impairment  Rewarming, IV Acute: (2) fluids and IV methylpred- nisolone and antibiotics for ?UTI and respiratory infections were given. Normothermia within 24 hours. Full clinical recovery in 4 weeks  Passive Acute (1) rewarming. Normothermia in 24 hours. Full clinical recovery in 7 days  Rewarming. Acute: (2) Normothermia in 3 days. Residual physical and cognitive deficits  NK Chronic with acute episode: (2) Chronic with  NK acute episodes (NK)  Antibiotics, IV Acute: (6) fluids. Initially recovered then further deterioration within a week (33.1[degrees]C) stupor and severe hypotension. Within 2 weeks a 3rd episode of hypothermia (31.2[degrees]C), bradycardia, and hypotension. She was treated with droxidopa and then discharged once normothermic and stable  Chronic with acute episodes Spontaneous (6) improvement and discharge with a T of 35.2 [degrees]C Passive rewarming. Then antibiotics and respiratory  assistance for Acute (6) ?SUO. Full clinical recovery in 6 weeks. Five monthly IV methylpred/ nisolone infusions (1 g/ month)  Full clinical NK recovery  Antibiotics for Acute (1) sepsis and 3 steroid injections. Full clinical recovery within days 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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