A patient with intractable posthypoxic myoclonus (Lance-Adams syndrome) treated with sodium oxybate.
We describe a young man who, after near-fatal cardiac arrest, recovered cognitively but was completely disabled by a severe form of PHM refractory to treatment with standard antimyoclonic drugs. The patient experienced dramatic improvement when sodium oxybate was administered.
A 16-year-old male, with a history of recurrent asthma, presented in cardiopulmonary arrest due to spontaneous bilateral pneumothorax. Spontaneous circulation returned after approximately seven minutes of advanced cardiac life support. Pneumothoraces were treated and he was transferred to the intensive care unit, where he was ventilated, sedated, paralysed and treated with hypothermia. When pharmacological paralysis and hypothermia were discontinued and sedation decreased a day later, a myoclonic status began despite treatment with midazolam and phenobarbitone. An electroencephalogram (EEG) study showed continuous spikes, polyspikes and slow wave diffuse activity requiring resumption of propofol. On the fifth day after arrest, the sedation was reduced again. The patient was alert and generalised myoclonus was present during rest and was induced by any kind of external stimulation. Antimyoclonic drugs were progressively administered, including piracetam (36 g/day intravenously), subsequently replaced by levetiracetam (4000 mg/day p.o.), clonazepam (11.25 mg/day intravenously), sodium valproate (2200 mg/day intravenously) and 5-hydroxytryptophan (1200 mg/day p.o.), obtaining only minimal transient antimyoclonic benefit. A brain MRI demonstrated bilateral hyperintensity at the level of the caudate, putamen and pallidum, consistent with hypoxic injury (Figure 1). In this circumstance an EEG showed diffuse alpha 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 attempts to follow commands or speak triggered severe myoclonus of the limbs and trunk. Negative myoclonic jerks were present affecting the distal arms. He was bed-bound and totally dependent as a result of involuntary movements.
Given the refractory nature of the disorder, 35 days post cardiac arrest, after obtaining consent from the patient and his parents, we embarked on an empiric trial with the off-label drug sodium oxybate. The dose and timing of all concurrent medications were unchanged throughout. To consider the potential effectiveness of sodium oxybate, we evaluated the anti-myoclonic effect of ethanol, administering 95% ethanol intravenously at a dose of 7.6 g/10 ml over three minutes. Within one minute of completion of infusion, myoclonic jerks disappeared, returning 15 minutes later. After the positive result obtained with the ethanol test, sodium oxybate was administered increasing progressively the dose over a period of seven weeks, and its efficacy was evaluated employing the Unified Myoclonus Rating Scale (1). For each dose increase we observed a reduction of myoclonus (Table 1). Sodium oxybate caused somnolence which, however, waned over the ensuing week. The dose of 2.5 g every four hours produced gastrointestinal distress and somnolence and was therefore reduced to 2 g every four hours. Under this regimen, all items of the Unified Myoclonus Rating scale improved (with the exception of negative myoclonus) and, in particular, myoclonus at rest was suppressed (Table 1). Physician rating of global disability (section 6 of Table 1) decreased from severe (4) to moderate (2). Remarkable was the daytime dose tolerance without significant sedation, despite the association with four other antimyoclonic drugs.
[FIGURE 1 OMITTED]
Transient cerebral hypoxia
Cardiac arrest causes global cerebral hypoxia/ ischaemia, but some regions of the brain are more vulnerable than others (2). The CAI and CA4 regions of the hippocampus, middle laminae of the neocortex, reticular nucleus of the thalamus, amygdala, cerebellar vermis, caudate nucleus and the pars reticulata of the substantia nigra are particularly vulnerable. Injury to cortical and thalamic neurones results in post-hypoxic coma (2). Injury to the basal ganglia, thalamus, midbrain and cerebellum can cause movement disorders, including myoclonus, Parkinsonism, dystonia, chorea and tremor (3). Although rarely, movement disorders can also persist after recovery of consciousness and, as in our patient, can deeply compromise the quality of life. The reason why patients with similar hypoxic cerebral insults develop dissimilar movement disorders is not known (3).
Myoclonus is a hyperkinetic movement disorder characterised by the occurrence of rapid, involuntary, irregular jerks that cannot be consciously suppressed. Myoclonus can occur spontaneously at rest, in response to sensory stimuli or with voluntary movements. Another clinical aspect is the distribution: generalised, segmental, multifocal or focal. Myoclonus can have many anatomical sources: cortex, subcortical centres, brainstem, spinal cord and peripheral nerves. It is a symptom that occurs in a variety of metabolic and neurological disorders (Table 2). Cerebral hypoxia, neurodegenerative disease and epileptic syndromes represent the main underlying causes (4).
There are two types of PHM; acute and chronic. Acute PHM typically begins within 24 hours from the hypoxic insult, occurs in patients who are deeply comatose and, by some authors, it is also called myoclonic status epilepticus, despite the lack of definitive evidence that these movements represent epileptic activity (3). It occurs in approximately 30 to 40% of comatose survivors of cardiac arrest and is associated with a poor prognosis. The treatment of myoclonic jerks in acute PHM is difficult (generally requiring intravenous anaesthetic agents) and of questionable usefulness besides the 'cosmetic' effect.
Chronic PHM typically occurs within a few days to a few weeks after the hypoxic injury. It is a rare but devastating complication of near-fatal cardiopulmonary arrest. First described by Lance and Adams in 1963 (5), it is a multifocal action myoclonus in combination with stimulus-sensitive, bilateral and generalised jerks, and usually accompanied by dysmetria, dysarthria and ataxia, with relative preservation of higher cognitive functions. The clinical feature is quite distinct and in most cases, the diagnosis can be determined on clinical pictures with a good degree of diagnostic definiteness. MRI can show loss of grey-white matter distinction and selective neuronal injuries in the grey deep nuclei, but usually it is not specific of PHM. EEG can evidence the presence of well-defined spike, polyspike or spike-wave in association with the burst of EMG activation indicating a distinct abnormality (i.e. an epileptic mechanism) and as in this patient, the simple EEG may not reveal a precise abnormality which can be associated with the myoclonic movements. In particular cases, EEG-EMG polygraphy with back-averaging and somatosensory evoked potentials are required to confirm the diagnosis.
Myoclonus may originate from either cortical or subcortical foci, although both forms may coexist (6). The pathophysiology of PHM is still unknown, although it is likely that subcortical neuronal networks including the ventrolateral thalamus are involved'. Alterations in multiple neurochemical systems have been reported in animal and human studies of PHM. It has been noted that abnormalities within the serotonin system and/or a loss of GABAergic inhibition may influence the pathophysiologic mechanism of PHM (7-8).
Treatment of PHM
Therapy of PHM is empiric, based on class III evidence (Table 3). Levetiracetam, piracetam, sodium valproate and clonazepam are the four most effective agents used (3-4). Antimyoclonic agents are usually used in combination and it is rare for one agent to achieve control of myoclonus. Primidone, zonisamide and 5-hydroxytryptophan are useful in some cases. Phenobarbital, phenytoin and carbamazepine are infrequently helpful. Earlier reports have shown that sodium oxybate was effective in reducing myoclonus in a few patients affected by myoclonus-dystonia and posthypoxic myoclonus (9-10).
Sodium oxybate is the sodium salt used for the oral administration of [gamma]-hydroxybutyric acid (GHB), an endogenous short chain fatty acid synthesised within the central nervous system mostly from its precursor GABA. Evidence suggests a role for GHB as a neuromodulator/neurotransmitter (11). Although the mechanism of action of sodium oxybate is not well understood, after exogenous administration, most of its effects appear to involve GHB and GABA(B) receptors, and modulation of dopaminergic signaling (11). Specific receptors for GHB are located in the thalamus, hippocampus and Cortex (11).
Sodium oxybate is licensed in some European countries for the treatment of alcohol withdrawal, and in the United States and Canada only for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy. Administration of sodium oxybate must be carefully titrated. Adverse events include respiratory insufficiency. Therefore high doses of sodium oxybate should be administered in an appropriate clinical setting.
PHM is a rare but devastating complication of near-fatal cardiac arrest. While the patient is conscious, he or she is disabled by rapid, diffuse, uncontrollable jerks.
The therapy of PHM is empiric. Levetiracetam, piracetam, clonazepam and valproic acid are the first-line agents in the treatment of PHM. A combination of medications is often required.
Sodium oxybate is an off-label agent which can be used in patients with ethanol-sensitive intractable PHM.
We thank the patient and his family for their participation and insight and Dr Silvana Franceschetti (Istituto Carlo Besta, Milano) for her clinical suggestions.
Address for reprints: Dr R. Imberti, 2nd Department of Anaesthesiology and Critical Care Medicine, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
Accepted for publication on October 23, 2008.
(1.) Frucht SJ, Leurgans SE, Hallet M, Fahn S. The Unified Myoclonus Rating Scale. In: Myoclonus and paroxysmal dyskinesias. Advances in neurology. Vol.89. Philadelphia: Lippincott Williams and Wilkins 2002. p. 361-376.
(2.) Hoesch RE, Koenig MA, Geocadin RG. Coma after global ischemicbrain injury: pathophysiology and emerging therapies. Crit Care Clin 2008; 24:25-44.
(3.) Caviness JN, Brown P Myoclonus: current concepts and recent advances. Lancet Neurol 2004; 3:598-607.
(4.) Venkatesan A, Frucht S. Movement disorders after resuscitation from cardiac arrest. Neurol Clin 2006; 24:123-132.
(5.) Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 1963; 86:111-136.
(6.) Frucht S, Fahn S. The clinical spectrum of posthypoxic myoclonus. Mov Disord 2000; 15 (Suppl 1):2-7.
(7.) Truong DD, Kirby M, Kanthasamy A, Matsumoto RR. Posthypoxic myoclonus animal models. Adv Neurol 2002; 89:295-306.
(8.) Matsumoto RR, Truong DD, Nguyen KD, Dang AT, Hoang TT, Vo PQ et al. Involvement of GABA(A) receptors in myoclonus. Mov Disord 2000; 15 (Suppl 1):47-52.
(9.) Priori A, Bertolasi L, Pesenti A, Cappellari A, Barbieri S. Gamma- hydroxybutyric acid for alcohol-sensitive myoclonus with dystonia. Neurology 2000; 54:1706.
(10.) Frucht SJ, Bordelon Y, Houghton WH. Marked amelioration of alcohol-responsive posthypoxic myoclonus by gammahydroxybutyric acid (Xyrem). Mov Disord 2005; 20:745-751.
(11.) Pardi D, Black J. Gamma-Hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs 2006; 20:993-1018.
R. Arpesella *, C. Dallocchio ([dagger]), C. Arbasino ([dagger]), R. Imberti ([double dagger]), R. Martinotti *, S. J. Frucht ([section])
Department of Intensive Care and Emergency Unit, Ospedale Civile, Voghera, Italy
* M.D., Intensivist.
([dagger]) M.D., Neurologist, Division of Neurology, Ospedale Civile.
([double dagger]) M.D., Intensivist, 2nd Department of Anaesthesiology and Critical Care Medicine, Fondazione IRCCS Policlinico S. Matteo, Pavia.
([section]) M.D., Neurologist, Department of Neurology, Columbia University Medical Center, New York, United States of America.
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 0 g 1 g/8h 2 g/8 h range 1 (self-assessment) 0-60 60 60 60 2 (at rest) 0-128 128 120 116 3 (stimulus-sensitive) 0-17 17 17 17 4 (action) 0-160 112 112 108 5 (functional performance) 0-20 20 20 20 6 (global disability) 0-4 4 4 4 7 (negative myoclonus) 0-1 1 1 1 8 (severity negative myoclonus) 0-3 3 3 3 Weeks 0 1 2 Sodium oxybate UMRS section 2 g/6 h 2 g/5 h 2 g/4 h 1 (self-assessment) 58 56 52 2 (at rest) 41 29 0 3 (stimulus-sensitive) 15 13 13 4 (action) 66 48 44 5 (functional performance) 19 17 14 6 (global disability) 4 3 3 7 (negative myoclonus) 1 1 1 8 (severity negative myoclonus) 3 3 1 Weeks 3 4 5 Sodium oxybate UMRS section 2.5 g/4 h 2 g/4 h 1 (self-assessment) 48 49 2 (at rest) 0 0 3 (stimulus-sensitive) 10 10 4 (action) 40 42 5 (functional performance) 14 14 6 (global disability) 2 2 7 (negative myoclonus) 1 1 8 (severity negative myoclonus) 1 1 Weeks 6 7 UMRS = Unified Myoclonus Rating Scale. TABLE 2 List of possible disorders in which myoclonus can occur (4) Metabolic encephalopathy (post-hypoxia, electrolytes imbalance, hepatic failure, renal failure, hypoglycaemia, hyperthyroidism) Drugs (narcotics, antiarrhythmics, psychiatric medication, lithium, cephalosporins, trimethoprim-sulphamethoxazole, L-dopa, amantadine) Toxics (marijuana, heavy metals, strychnine) Physical encephalopathy (post-traumatic, sunstroke) Paraneoplastic encephalopathy Infectious/post-infectious encephalitis (herpes simplex virus, arbour virus, AIDS, SSPE) Dementia (Creutzfeld-Jakob disease, Alzheimer disease, frontotemporal dementia, Lewy body dementia) Basal ganglia and spinocerebellar degeneration (Huntington's disease, Parkinson's disease, PSP, MSA, Friedrich's ataxia, SCA1, SCA2, Wilson's disease) Lipid storage disease (Laforabody disease, Tay-Sachs disease, GM2 gangliosidosis) Focal central nervous system lesions Certain types of epilepsy (childhood myoclonic epilepsy, epileptic myoclonic jerks, infantile spasms, epilepsia partialis continua, photosensitive myoclonus) Essential myoclonus (hereditary, sporadic, myoclonus-dystonia) Physiological myoclonus (sleep jerks, exercise, hiccup) SSPE=subacute sclerosing panencephalitis, PSP=progressive supranuclear paralysis, MSA=multiple system atrophy, SCA=spinocerebellar ataxia. TABLE 3 Drugs often useful in the treatment of post-hypoxic myoclonus (3-4) Common dose Adverse effects Levetiracetam 1000 *-4000 mg/day well tolerated, minor decrease in RBC, Hb, Ht and WBC Valproic acid 200 *-2200 mg/day hepatic failure, pancreatitis, thrombocytopenia Clonazepam 0.5 *-15 mg/day drowsiness Piracetam 12 *-36 g/day well tolerated Zonisamide 50 *-600 mg/day sedation, leucopenia, elevation liver transaminases 5-HTP [section] 100 *-1500 mg/day gastritis, skin rash Sodium oxybate # 4 *-12 g/day drowsiness, euphoria, respiratory depression * Initial dose, [section] generally associated with carbidopa to avoid nausea, # use of sodium oxybate should be considered experimental.
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|Author:||Arpesella, R.; Dallocchio, C.; Arbasino, C.; Imberti, R.; Martinotti, R.; Frucht, S.J.|
|Publication:||Anaesthesia and Intensive Care|
|Article Type:||Clinical report|
|Date:||Mar 1, 2009|
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