Sudden Death: An Uncommon Occurrence in Dementia with Lewy Bodies

CASE PRESENTATION

A 75-year-old woman presented to the emergency department with repeated transient loss of consciousness. The year before admission she had experienced three episodes of unconsciousness where she was found unresponsive next to the toilet with a snoring breath. This had been interpreted as epileptic seizures and was treated with valproate and levetiracetam.

During the last 6 months she had developed a progressive tremor of both arms and a slow gait with small steps. Three weeks before admission symptoms had worsened rapidly; she could hardly walk and had strongly fluctuating attention. No excessive sweating or cold hands were mentioned. She was mildly constipated.

Neurological examination revealed reduced and fluctuating attention, bradyphrenia, disorientation in time and place, short-term memory problems, and verbal fluency problems. Mini-mental state examination (MMSE) fluctuated from 16/30 to 23/30. She showed loss of facial expression, a bilateral arm tremor in resting, symmetrical rigidity in all extremities, and inability to walk. During admission severe orthostatic hypotension was noted: Blood pressure dropped from a recumbent 146/80 mmHg to 84/51 mmHg after 3 minutes of standing, without compensatory tachycardia. A bladder scan revealed urinary retention. The patient was given compression stockings and fludrocortisone (0.2 mg daily). Both did not have a significant effect on orthostatic hypotension.

The differential diagnosis included dementia with Lewy bodies (DLB), Parkinson’s disease, multiple system atrophy (MSA), a paraneoplastic syndrome, and Creutzfeldt-Jakob disease.

Laboratory tests revealed an elevated C-reactive Protein (CRP) (32 mg/L) and a urinary tract infection. Magnetic resonance imaging (MRI) of the brain showed no abnormalities. Cerebrospinal fluid (CSF) analysis showed normal white blood-cell count, protein, and glucose, and 14-3-3 protein was negative. A combination of low amyloid-β42 (261 ng/L) with normal Tau (160 ng/L) and phospho-Tau (35 ng/L) was suggestive of DLB [4]. Electroencephalography (EEG) showed diffuse theta activity, without epileptiform activity. Dopamine transporter single photon emission computed tomography (DaT-SPECT) showed a symmetrically decreased uptake of dopamine at the putamen. The patient was treated with levodopa, which slightly improved the hypokinetic rigid syndrome.

Four weeks after admission the patient was found deceased in the bathroom. Autopsy revealed extensive Lewy body formation in the midbrain, limbic system, intermediate spinal cord, and medulla oblongata. Furthermore, a massive amount of Lewy bodies was seen in the paravertebral sympathetic ganglia (Fig. 1). There was hardly any atherosclerosis of the coronaryarteries.

DISCUSSION

We describe a woman with pathologically confirmed DLB who developed severe orthostatic hypotension and sudden death. We believe this was caused by extensive Lewy body involvement within the intermediolateral columns of the spinal cord, the autonomic ganglia, and sympathetic neurons, affecting either respiration or heart rhythm.

A retrospective analysis of autonomic symptoms in 28 patients with neuropathologically diagnosed DLB showed that 97% had autonomic failure [2]. Orthostatic hypotension was seen in 66% of patients, and in 28% of patients this led to repeated episodes of syncope. Orthostatic hypotension in DLB is usually caused by the loss of postganglionic sympathetic nervous function, and in some patients from preganglionic dysfunction [1]. Both in DLB and Parkinson’s disease autonomic failure can occur early in the course of the disease and can even be the initial symptom [2, 3].

Sudden death in patients with DLB has only sporadically been described as a result of severe autonomic failure [5]. In MSA acute cardiopulmonary arrest is the leading cause of death [6]. Beside inspiratory stridor, autonomic failure has been suggested as the underlying mechanism. A recent study demonstrated that MSA patients with sudden death showed a marked depletion of neurons in the spinal intermediolateral cell column, ventrolateral medulla, nucleus raphe, and arcuate nucleus, compared to MSA patients who did not die unexpectedly [7]. Medullary serotonergic neurons project to many autonomic nuclei in the medulla oblongata and spinal cord, which then influence the sympathetic outflow as well as thermal, respiratory, and cardiovascular regulation. Dysfunction of the regulation of these cardiovascular and respiratory systems could be responsible for sudden death in patients with MSA [7]. A similar mechanism might have led to the sudden death in our patient.

The repeated attacks of unconsciousness while visiting the bathroom at night are much more likely to have been due to syncope (i.e. failure of the systemic blood circulation), either due to orthostatic hypotension or due to a reflex syncope caused by increased vagal tone, rather than to epilepsy as had been assumed. This underscores the importance of a thorough medical history in identifying the cause of transient loss of consciousness [8].

Features suggestive of orthostatic syncope include a relation to body position and associated symptoms of feeling lightheaded, blurred vision, and coat-hanger pain [8] This can help differentiate true syncope from other causes of transient loss of consciousness (such as epilepsy) or from mimics, such as the sometimes dramatic (but poorly understood) fluctuations in alertness that patients with DLB can experience. Correctly identifying the cause of transient loss of consciousness will prevent exposing patients to possibly unnecessary treatment such asanticonvulsants.

Clinicians should be aware of sudden death as a possible complication in patients presenting with parkinsonism and autonomic dysfunction, and that this may occur in DLB as it does in MSA. Cardiological screening (including tilt-table testing) should be considered in patients with severe orthostatic hypotension and/or repeated attacks of unconsciousness, as pacemaker implantation could be indicated [9].

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

INDIVIDUAL CONTRIBUTIONS TO THE MANUSCRIPT

J.P. Molenaar: Identified and managed the case, performed the literature search, and made a substantial contribution to drafting of the manuscript