'Cold and Locked in': A Frozen Body and Frozen Eyes in End-Stage ALS.

Sir,

Amyotrophic lateral sclerosis (ALS) was thought to lead to neurodegeneration of somatic motor neurons but spare the oculomotor, sphincteric, and sensory neuronal functions. However, as ALS patients survive longer with tracheostomy and invasive ventilation (TIV); impairment of these have also been noticed in long survivors.[1] The average life expectancy in nonventilated ALS is around 2 years and <10% of cases live longer than 10 years.[2] Increasingly, patients with ALS have started opting for TIV (up to 10% of ALS patients in western countries and 45% in Japan).[3] TIV prolongs life expectancy in ALS by approximately 7 years.[4] A totally locked in state (TLS), defined as total paralysis of all voluntary and ocular muscles, develops in about 13–19% of patients, within 3 years of TIV.[5]

Comparatively, only a small number of patients in India opt for TIV, and there is scant data on TLS from India. We report two cases of ALS with a near TLS and ICU associated hypothermia.

A 62-year man presented with weakness of the right hand 16 months earlier. Electromyography had shown extensive denervation and reinnervation all four segments. He was diagnosed with ALS by the Gold coast criteria.[6] One year after onset, he required a TIV. He was admitted for a tracheostomy tube change. Examination revealed an emaciated male (body weight 30 kg) with grade 0/5 MRC power in all muscles, bifacial wasting with inability to close the eyelids fully. He also had generalised wasting and areflexia. He was occasionally able to communicate through eye blinks [Hayashi stage IV].[7] Oculomotor evaluation revealed slow horizontal saccades and downward saccades. Pursuit movements and vertical saccades were absent [Video 1]. Vertical and horizontal oculocephalic reflexes were preserved. He was hypothermic (34.4° C). Arterial blood gases and electrocardiogram were normal (no Osborn or J Waves). Routine blood tests including total WBC counts, serum lactate, blood cultures renal, liver, and thyroid function tests were normal. An extensive evaluation for causes of hypothermia was inconclusive. The ambient temperature in the ICU was noted to be 20° C.

He required continuous surface warming (bed warmer), multiple blankets, and warm IV fluids to maintain normothermia. Detailed history revealed the presence of cold intolerance (air conditioning) for the previous few months. He maintained normothermia only when the ICU ambient temperature rose to 31–32° C. 45 days later, he developed a lobar pneumonia, sepsis and succumbed.

The second case was a 55-year-old man with ALS of 4 years duration. After 6 months, his family opted for TIV. Four years later, he was in a TLS with total external ophthalmoplegia (Hayashi stage V) and no response to oculocephalic manoeuvres. During admission to ICU for repeated respiratory infections, he was noted to be emaciated and hypothermic (35° C). He also required similar warming measures to achieve normothermia. At home, in a non-air-conditioned room, he remained normothermic.

Human beings are endotherms that require generation of sufficient endogenous heat or dissipation of excess heat ['waste heat'] to maintain normothermia within a limited range of environmental temperature [Figure 1]. Beyond a certain range of temperature, internal homeostatic mechanisms are inadequate to maintain body temperature. We then require external aids to maintain normothermia such as external heat or cooling (fans, air conditioning, heaters, warm clothing, or other temperature control devices).

Figure 1

Heat generation and heat loss in human beings

The generation of internal heat is largely by two mechanisms. First, exothermic 'metabolic heat' is produced by various organs. Second, skeletal muscle constitute the largest proportion of body weight and contribute significantly to the whole-body metabolic rate (WBMR) [approximately ~40% of WBMR].[8] Muscle primarily utilizes nonshivering thermogenesis (NST) to generate heat, either by the uncoupling of oxidative phosphorylation (mitochondrial proton leak; 8–16% of WBMR) or by a sarco/endoplasmic reticulum calcium-ATPase pump, which accounts for 24–58% of WBMR.[9]

If these mechanisms are inadequate to generate heat, then muscle shivering is initiated (shivering thermogenesis or ST) to generate additional body heat (24–32% of WBMR during cold exposure). The causes of hypothermia are many [Figure 2].[1011] We hypothesize that the loss of nearly all his skeletal muscle led to a drastic reduction in both his myogenic NST and ST. As a result, he was unable to maintain normothermia with exposure to the ICU air conditioning.

Figure 2

Depiction of the different causes of hypothermia

A corollary can be drawn from hypothermia in sepsis.[12] In the early phase of sepsis, patients develop fever as an adaptive strategy. However, in the late phase of sepsis or in decompensated individuals, hypothermia occurs. Hypothermia can occur beneficially if the body resorts to an energy saving adaptive hypothermia to reduce tissue metabolic requirements (van't Hoff's rule, tissue metabolic requirements reduce by >10% for every 1°C drop in body temperature). More often, hypothermia is an ominous sign of energy depletion, decompensation, and impending death.

Depression, cognitive impairment, frontotemporal dementia, oculomotor dysfunction, and progressive loss of ability to communicate develop with time in ALS patients. Cranial motor impairment in ALS usually ascends from the bulbar muscles and occurs in the reverse order of the developmental sequence of the cranial motor nuclei, reflecting the older ontogenesis of oculomotor nuclei. Oculomotor abnormalities (OMA) are seen in around 10% of ALS patients as the disease progresses. The most common early OMA are smooth pursuit and saccadic abnormalities followed by supranuclear ophthalmoplegia and finally total external ophthalmoplegia. Initially, frontal oculomotor areas are involved in ALS, followed in the end stages by ocular motor neuron degeneration.[13]

Hayashi et al.[7] have proposed a five-stage classification system that describes the communication abilities of patients with advanced ALS. In stage I, patients can communicate through sentences. By stage II, communication is limited to one-word answers. By stage III, communication is limited to nonverbal yes/no responses. By stage IV, communicate is difficult due to uncertain yes/no responses. By stage V, the patient reaches TLS and cannot communicate by any means.

Our patients with ALS were in stages IV and V with TLS. Severe muscle loss precluded endothermic muscular heat generation necessary to maintain normothermia in a cold environment. Progressive degeneration of supranuclear followed by infranuclear oculomotor motor neurons must have produced the total external ophthalmoplegia.

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Conflicts of interest

There are no conflicts of interest.