Anaesth Intensive Care 2009; 37: 314-318

A patient with intractable posthypoxic myoclonus

(Lance-Adams syndrome) treated with sodium oxybate
R. Arpesella*, C. Dallocchio†, C. Arbasino†, R. Imberti‡, R. Martinotti*,
S. J. Frucht§
Department of Intensive Care and Emergency Unit, Ospedale Civile, Voghera, Italy

Summary
Posthypoxic myoclonus is a rare and devastating complication of near-fatal cardiopulmonary arrest. Despite
treatment with available anti-myoclonic agents, some patients may recover cognitively but remain completely
disabled by severe myoclonus. We report a 16-year-old patient with severe treatment-refractory posthypoxic
myoclonus, which improved markedly with administration of the drug sodium oxybate.
Key Words: posthypoxic myoclonus, Lance-Adams syndrome, cerebral hypoxia, sodium oxybate

With the widespread availability of cardio- When pharmacological paralysis and hypothermia
pulmonary resuscitation and intensive care units, an were discontinued and sedation decreased a day
increasing number of patients may survive near-fatal later, a myoclonic status began despite treatment
cardiopulmonary arrests. Posthypoxic myoclonus with midazolam and phenobarbitone. An electro-
(PHM) is a rare but devastating complication of these encephalogram (EEG) study showed continuous
events. spikes, polyspikes and slow wave diffuse activity
We describe a young man who, after near-fatal requiring resumption of propofol. On the fifth day
cardiac arrest, recovered cognitively but was after arrest, the sedation was reduced again. The
completely disabled by a severe form of PHM patient was alert and generalised myoclonus
refractory to treatment with standard anti- was present during rest and was induced by
myoclonic drugs. The patient experienced any kind of external stimulation. Anti-
dramatic improvement when sodium oxybate was myoclonic drugs were progressively administered,
administered. including piracetam (36 g/day intravenously),
subsequently replaced by levetiracetam (4000 mg/day
CASE HISTORY p.o.), clonazepam (11.25 mg/day intravenously),
A 16-year-old male, with a history of recurrent sodium valproate (2200 mg/day intravenously) and
asthma, presented in cardiopulmonary arrest due to 5-hydroxytryptophan (1200 mg/day p.o.), obtaining
spontaneous bilateral pneumothorax. Spontaneous only minimal transient antimyoclonic benefit. A
circulation returned after approximately seven brain MRI demonstrated bilateral hyperintensity
minutes of advanced cardiac life support. at the level of the caudate, putamen and pallidum,
Pneumothoraces were treated and he was transferred consistent with hypoxic injury (Figure 1). In
to the intensive care unit, where he was ventilated, this circumstance an EEG showed diffuse alpha
sedated, paralysed and treated with hypothermia. activity intermixed with theta rhythm.
Neurological examination performed while the
patient was under combined pharmacological
antimyoclonic therapy showed an alert young
man with severe myoclonus at rest. Even minimal
* M.D., Intensivist. attempts to follow commands or speak triggered
† M.D., Neurologist, Division of Neurology, Ospedale Civile. severe myoclonus of the limbs and trunk. Negative
‡ M.D., Intensivist, 2nd Department of Anaesthesiology and Critical Care
Medicine, Fondazione IRCCS Policlinico S. Matteo, Pavia. myoclonic jerks were present affecting the distal
§ M.D., Neurologist, Department of Neurology, Columbia University Medical arms. He was bed-bound and totally dependent as a
Center, New York, United States of America.
result of involuntary movements.
Address for reprints: Dr R. Imberti, 2nd Department of Anaesthesiology
and Critical Care Medicine, Fondazione IRCCS Policlinico S. Matteo, Pavia, Given the refractory nature of the disorder, 35 days
Italy. post cardiac arrest, after obtaining consent from the
Accepted for publication on October 23, 2008. patient and his parents, we embarked on an empiric
Anaesthesia and Intensive Care, Vol. 37, No. 2, March 2009
 Case Report 315

trial with the off-label drug sodium oxybate. The employing the Unified Myoclonus Rating Scale1.
dose and timing of all concurrent medications were For each dose increase we observed a reduction
unchanged throughout. To consider the potential of myoclonus (Table 1). Sodium oxybate caused
effectiveness of sodium oxybate, we evaluated the somnolence which, however, waned over the ensuing
anti-myoclonic effect of ethanol, administering 95% week. The dose of 2.5 g every four hours produced
ethanol intravenously at a dose of 7.6 g/10 ml over gastrointestinal distress and somnolence and was
three minutes. Within one minute of completion of therefore reduced to 2 g every four hours. Under
infusion, myoclonic jerks disappeared, returning this regimen, all items of the Unified Myoclonus
15 minutes later. After the positive result obtained Rating scale improved (with the exception of negative
with the ethanol test, sodium oxybate was myoclonus) and, in particular, myoclonus at rest
administered increasing progressively the dose over a was suppressed (Table 1). Physician rating of global
period of seven weeks, and its efficacy was evaluated disability (section 6 of Table 1) decreased from severe

Figure 1: Axial T1-weighted (A) and coronal T2-weighted (B) images obtained a few days after insult show
increased signal intensity in basal ganglia consistent with cerebral hypoxia.

Table 1
Unified Myoclonus Rating Scale subscores at baseline while the patient was treated with levetiracetam, clonazepam, sodium valproate and
5-hydroxytryptophan, and during the administration of incremental doses of sodium oxybate

Sodium oxybate
UMRS section Score range 0g 1 g/8 h 2 g/8 h 2 g/6 h 2 g/5 h 2 g/4 h 2.5 g/4 h 2 g/4 h
1 (self-assessment) 0-60 60 60 60 58 56 52 48 49
2 (at rest) 0-128 128 120 116 41 29 0 0 0
3 (stimulus-sensitive) 0-17 17 17 17 15 13 13 10 10
4 (action) 0-160 112 112 108 66 48 44 40 42
5 (functional performance) 0-20 20 20 20 19 17 14 14 14
6 (global disability) 0-4 4 4 4 4 3 3 2 2
7 (negative myoclonus) 0-1 1 1 1 1 1 1 1 1
8 (severity negative myoclonus) 0-3 3 3 3 3 3 1 1 1
Weeks 0 1 2 3 4 5 6 7

UMRS=Unified Myoclonus Rating Scale.

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316 R. Arpesella, C. Dallocchio et al

(4) to moderate (2). Remarkable was the daytime Table 2

dose tolerance without significant sedation, despite List of possible disorders in which myoclonus can occur4
the association with four other antimyoclonic drugs. Metabolic encephalopathy (post-hypoxia, electrolytes imbalance,
hepatic failure, renal failure, hypoglycaemia, hyperthyroidism)
DISCUSSION Drugs (narcotics, antiarrhythmics, psychiatric medication,
Transient cerebral hypoxia lithium, cephalosporins, trimethoprim-sulphamethoxazole,
L-dopa, amantadine)
Cardiac arrest causes global cerebral hypoxia/
ischaemia, but some regions of the brain are more Toxics (marijuana, heavy metals, strychnine)
vulnerable than others2. The CA1 and CA4 regions of Physical encephalopathy (post-traumatic, sunstroke)
the hippocampus, middle laminae of the neocortex, Paraneoplastic encephalopathy
reticular nucleus of the thalamus, amygdala, Infectious/post-infectious encephalitis (herpes simplex virus,
cerebellar vermis, caudate nucleus and the pars arbour virus, AIDS, SSPE)
reticulata of the substantia nigra are particularly Dementia (Creutzfeld-Jakob disease, Alzheimer disease,
vulnerable. Injury to cortical and thalamic neurones frontotemporal dementia, Lewy body dementia)
results in post-hypoxic coma2. Injury to the basal Basal ganglia and spinocerebellar degeneration (Huntington’s
ganglia, thalamus, midbrain and cerebellum can disease, Parkinson’s disease, PSP, MSA, Friedrich’s ataxia,
SCA1, SCA2, Wilson’s disease)
cause movement disorders, including myoclonus,
Parkinsonism, dystonia, chorea and tremor3. Lipid storage disease (Lafora body disease, Tay-Sachs disease,
GM2 gangliosidosis)
Although rarely, movement disorders can also
Focal central nervous system lesions
persist after recovery of consciousness and, as in
our patient, can deeply compromise the quality of Certain types of epilepsy (childhood myoclonic epilepsy,
epileptic myoclonic jerks, infantile spasms, epilepsia partialis
life. The reason why patients with similar hypoxic continua, photosensitive myoclonus)
cerebral insults develop dissimilar movement
Essential myoclonus (hereditary, sporadic, myoclonus-dystonia)
disorders is not known3.
Physiological myoclonus (sleep jerks, exercise, hiccup)
Myoclonus
SSPE=subacute sclerosing panencephalitis, PSP=progressive
Myoclonus is a hyperkinetic movement disorder supranuclear paralysis, MSA=multiple system atrophy,
characterised by the occurrence of rapid, involuntary, SCA=spinocerebellar ataxia.
irregular jerks that cannot be consciously suppressed.
Myoclonus can occur spontaneously at rest, in Chronic PHM typically occurs within a few
response to sensory stimuli or with voluntary days to a few weeks after the hypoxic injury. It is
movements. Another clinical aspect is the a rare but devastating complication of near-fatal
distribution: generalised, segmental, multifocal or cardiopulmonary arrest. First described by Lance and
focal. Myoclonus can have many anatomical sources: Adams in 19635, it is a multifocal action myoclonus
cortex, subcortical centres, brainstem, spinal cord in combination with stimulus-sensitive, bilateral
and peripheral nerves. It is a symptom that occurs and generalised jerks, and usually accompanied
in a variety of metabolic and neurological disorders by dysmetria, dysarthria and ataxia, with relative
(Table 2). Cerebral hypoxia, neurodegenerative preservation of higher cognitive functions. The
disease and epileptic syndromes represent the main clinical feature is quite distinct and in most cases,
underlying causes4. the diagnosis can be determined on clinical pictures
with a good degree of diagnostic definiteness. MRI
Posthypoxic myoclonus can show loss of grey-white matter distinction and
There are two types of PHM; acute and chronic. selective neuronal injuries in the grey deep nuclei,
Acute PHM typically begins within 24 hours from but usually it is not specific of PHM. EEG can
the hypoxic insult, occurs in patients who are deeply evidence the presence of well-defined spike,
comatose and, by some authors, it is also called polyspike or spike-wave in association with the
myoclonic status epilepticus, despite the lack of burst of EMG activation indicating a distinct
definitive evidence that these movements represent abnormality (i.e. an epileptic mechanism) and as in
epileptic activity3. It occurs in approximately 30 to this patient, the simple EEG may not reveal a precise
40% of comatose survivors of cardiac arrest and is abnormality which can be associated with the
associated with a poor prognosis. The treatment of myoclonic movements. In particular cases, EEG-
myoclonic jerks in acute PHM is difficult (generally EMG polygraphy with back-averaging and
requiring intravenous anaesthetic agents) and of somatosensory evoked potentials are required to
questionable usefulness besides the ‘cosmetic’ effect. confirm the diagnosis.
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 Case Report 317

Myoclonus may originate from either cortical or most of its effects appear to involve GHB and
subcortical foci, although both forms may coexist6. GABA(B) receptors, and modulation of
The pathophysiology of PHM is still unknown, dopaminergic signaling11. Specific receptors for
although it is likely that subcortical neuronal GHB are located in the thalamus, hippocampus and
networks including the ventrolateral thalamus are cortex11.
involved6. Alterations in multiple neurochemical Sodium oxybate is licensed in some European
systems have been reported in animal and countries for the treatment of alcohol withdrawal,
human studies of PHM. It has been noted that and in the United States and Canada only for
abnormalities within the serotonin system and/or the treatment of cataplexy and excessive daytime
a loss of GABAergic inhibition may influence the sleepiness in patients with narcolepsy. Administration
pathophysiologic mechanism of PHM7,8. of sodium oxybate must be carefully titrated. Adverse
events include respiratory insufficiency. Therefore
Treatment of PHM high doses of sodium oxybate should be administered
Therapy of PHM is empiric, based on class III in an appropriate clinical setting.
evidence (Table 3). Levetiracetam, piracetam, sodium
valproate and clonazepam are the four most effective CONCLUSIONS
agents used3,4. Antimyoclonic agents are usually
PHM is a rare but devastating complication of
used in combination and it is rare for one agent to
near-fatal cardiac arrest. While the patient is
achieve control of myoclonus. Primidone, zonisamide
conscious, he or she is disabled by rapid, diffuse,
and 5-hydroxytryptophan are useful in some cases.
uncontrollable jerks.
Phenobarbital, phenytoin and carbamazepine are
The therapy of PHM is empiric. Levetiracetam,
infrequently helpful. Earlier reports have shown that
piracetam, clonazepam and valproic acid are the
sodium oxybate was effective in reducing myoclonus
first-line agents in the treatment of PHM. A
in a few patients affected by myoclonus-dystonia and
combination of medications is often required.
posthypoxic myoclonus9,10.
Sodium oxybate is an off-label agent which can be
Sodium oxybate is the sodium salt used for the
used in patients with ethanol-sensitive intractable
oral administration of γ-hydroxybutyric acid (GHB),
PHM.
an endogenous short chain fatty acid synthesised
within the central nervous system mostly from its
ACKNOWLEDGEMENTS
precursor GABA. Evidence suggests a role for GHB
We thank the patient and his family for
as a neuromodulator/neurotransmitter11. Although
their participation and insight and Dr Silvana
the mechanism of action of sodium oxybate is not
Franceschetti (Istituto Carlo Besta, Milano) for her
well understood, after exogenous administration,
clinical suggestions.

Table 3
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