Journal Identification = EPD Article Identification = 0626 Date: March 21, 2014 Time: 12:25 pm

Clinical commentary with video sequences

Epileptic Disord 2014; 16 (1): 107-11 Alcohol-responsive epilepsia partialis continua

Trevor A Steve, Donald W Gross Division of , Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada

ABSTRACT – Epilepsia partialis continua is typically associated with lesions of the cerebral cortex. However, subcortical lesions can also cause this condition. We present a patient with epilepsia partialis continua who failed to respond to conventional medications but experienced a dramatic transient response to alcohol and a subsequent response to primidone. This pattern of sensitivity, which is similar to that seen in essen- tial tremor, has led to the hypothesis that the two disorders are associated with pathology within the same anatomical network. A new pathophys- iological model is thus proposed for the occurrence of epilepsia partialis continua in both cortical and subcortical disease processes. [Published with video sequences] Key words: epilepsia partialis continua, myoclonus, essential tremor, tremor

Epilepsia partialis continua (EPC) both cortical and subcortical lesions is defined as “continuous muscle (Guerrini, 2009). jerks of cortical origin” (Cockerell Essential tremor (ET) consists of et al., 1996). Patients with EPC postural-kinetic hand tremor and suffer from infrequent generalised variable involvement of other body and medically intractable regions. A striking feature in ET myoclonic jerks. The most com- is a dramatic temporary response mon causes of EPC are Rasmussen’s of the tremor to alcohol. Many , tumours, , and patients also experience a moder- focal cortical dysplasia. ate to marked improvement with The pathophysiology of EPC is primidone (Elble, 2009). The patho- incompletely understood (Guerrini, physiology of ET is believed to 2009). It is typically associated with involve “tremorogenic oscillation lesions in the contralateral cerebral and synchrony in motor networks”, cortex (Cockerell et al., 1996). How- involving the inferior olive, cere- ever, subcortical pathology can also bellum, and cerebral cortex (Elble, cause EPC (Juul-Jensen and Denny- 2009). We report a case of EPC Correspondence: Donald W Gross Brown, 1966). The role of subcortical which was alcohol and primidone 2E3.19 Walter Mackenzie Health Sciences structures in maintaining cortical responsive. Given the similarities Centre, epileptic activity remains unclear. of pharmacological sensitivity, we 8440 112 St NW, Presently, “no single mechanism” hypothesize overlap in the anatom- Edmonton T6G 2B7, Canada has been proposed to account ical network involved in ET and for the occurrence of EPC with EPC. doi:10.1684/epd.2014.0626

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T.A. Steve, D.W. Gross

Case Study that after having consumed several alcoholic bever- ages, his EPC resolved acutely and his hand function In 1998, a 31-year-old, right-handed male developed essentially improved to normal. At this time, he was new onset of continuous twitching of his right middle able to pick up a grain of rice with chopsticks, some- finger. The movements remained restricted to this thing that would have been impossible in his prior finger and were not accompanied by alteration of con- state. The next morning, his EPC had not only returned, sciousness. The patient did not seek medical attention but transiently worsened. and the twitching resolved spontaneously after three Based on the patient’s report of alcohol responsive- weeks. ness, primidone was started at a dose of 125 mg daily. The twitching returned again without provocation Within days of starting on this medication, after nearly in 2004. Over the course of five days, the move- seven years of continuous EPC, his movements com- ments spread sequentially to contiguous fingers and pletely disappeared. In association with this, his right the hand, and the patient then had a generalised hand function again improved dramatically (he was lasting two minutes. Following the generalised able to shave with his right hand). After approximately tonic-clonic convulsion, the patient continued to have one week, the movements returned. constant rhythmic twitching of the right arm (video With increasing doses of primidone, both the EPC sequence). His right upper extremity was rendered and motor function improved, but complete con- non-functional by the movements. Initial treatment trol was not obtained. A trial of propranolol had with valproic acid, carbamazepine, and phenytoin was no effect on the movements, suggesting peripheral unsuccessful. Clonazepam and levetiracetam were mechanisms did not play a major role in our patient partially effective, but despite these medications, the (Elble, 2009). Ethosuximide, which acts via inhibi- movements persisted. tion of low-threshold (T-type) calcium channels, also The EEG showed continuous rhythmic delta activ- had no effect on the movements. Based on reports ity in the left frontal-central-parietal region. An MRI of alcohol-responsive myoclonus responding well to performed the day following his generalised convul- gamma-hydroxybutyrate, this medication was tried for sion showed a focal region of increased T2 signal in one week (Frucht et al., 2005). The patient reported the left hemisphere, adjacent to the precentral sul- worsening of EPC during this trial as well as excess cus (figure 1A). This region demonstrated restricted sedation, and the medication was therefore discon- diffusion but not gadolinium enhancement. The CSF tinued. His current medications are levetiracetam at examination showed no cells and normal protein. 500 mg once daily, oxcarbazepine at 600 mg twice daily, As the continuous focal motor seizures failed to clonazepam at 0.5 mg twice daily, and primidone at respond to , aggressive management 375 mg twice daily. He presently remains disabled by was attempted. A sedating dose of intravenous propo- continuous twitching of the right hand and is unable fol eliminated the movements, but they returned when to write or shave. the infusion was discontinued. Propofol and pento- barbital in combination were then titrated to burst suppression, and the patient was maintained in coma Discussion for 48 hours. During this time, EPC was again abolish- ed, but the movements recurred immediately after dis- This report describes a patient with severe medically continuation of the anaesthetic. intractable EPC. Investigation revealed a transient The patient continued to have EPC over the next T2 hyperintensity adjacent to the left precentral several years. Some benefit was noted with , sulcus, likely related to ongoing seizure activity in but this medication was stopped due to development a location typical for EPC (Cockerell et al., 1996). of kidney stones. Oxcarbazepine was partially effec- Follow-up imaging ruled out stroke and tumour as tive and was continued. No significant improvement diagnostic possibilities. The negative cerebrospinal was achieved despite treatment with lacosamide, intra- fluid examination made encephalitis unlikely. The age venous solumedrol, and the modified Atkin’s diet. of presentation is atypical for focal cortical dysplasia. He suffered his only additional generalised seizure The patient did not develop progressive hemispheric in 2006. EPC remained essentially continuous and was atrophy characteristic of adult-onset Rasmussen’s, associated with major functional impairment of the use and did not respond to a course of corticosteroids. of his right hand. Repeat MRI in 2010 demonstrated Therefore, the underlying aetiology of EPC in this case atrophy of the cerebral cortex adjacent to the pre- remains uncertain. central sulcus, without evidence of T2 hyperintensity The response to alcohol and primidone in this patient (figure 1B). was dramatic, resulting in temporary, complete reso- In July of 2011, the patient presented to the clinic lution of EPC, and requires mechanistic explanation. having made an unusual observation. He recounted Primidone does have anticonvulsant effects, but the

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A

B

Figure 1. (A) Initial fluid-attenuated inversion recovery (FLAIR) MRI showing increased T2 signal in the cerebral cortex adjacent to the left precentral sulcus. (B) Follow-up FLAIR brain MRI performed six years later showing resolution of T2 signal abnormality and cortical atrophy adjacent to the precentral sulcus.

patient was refractory to AEDs which act by various and primidone is believed to act in a similar fashion mechanisms. Given the limited response of the EPC (Elble, 2009). Firstly, alcohol is capable of blocking to conventional anticonvulsants, we hypothesize that T-type calcium channels in the inferior olive (Sinton alcohol and primidone most likely acted in this patient et al., 1989). These channels are thought to be integral via a similar mechanism to that in Essential Tremor (ET). to the pathophysiology of ET by setting up excessive Animal studies have suggested that alcohol eliminates excitation of cerebellar Purkinje cells via the climbing ET by three mechanisms (Mostile and Jankovic, 2010), fibres (Mostile and Jankovic, 2010). Given the lack of

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T.A. Steve, D.W. Gross

Sensorimotor Mossy fibers cortex

Golgi cell Granule cell

Purkinje cell Cortico-pontine tract

A Parallel fibers

1 Basket/stellate cell Pontine nuclei

B 2

Thalamus VA/VL

Deep cerebellar nuclei

Climbing fiber Inferior olive neuron

Figure 2. Model depicting the proposed involvement of cerebellar micro-circuits in the pathophysiology of epilepsia partialis continua. Alcohol and primidone inhibit type 1 metabotropic glutamate receptors (A) at the climbing fibre-purkinje cell synapse (1). Ethanol and mysoline also normalise glutamate concentrations in the deep cerebellar nuclei (2), antagonising the activity of the N-methyl-D- aspartate (NMDA) glutamate receptor (B).

response of this patient to ethosuximide, it is unlikely responsible for this patient’s EPC was also cortical. that this mechanism plays an important role in this However, we hypothesize that the responsiveness to patient. The climbing fibre-Purkinje cell synapse is the alcohol and primidone is most likely explained by site of a second action, whereby alcohol is an effec- involvement of the cerebellar micro-circuits (figure 2). tive inhibitor of the metabotropic glutamate receptor Diffuse regions of cortex contribute axons to the (Carta et al., 2006). Finally, alcohol has been shown cortico-pontine tract, which is the main source of to normalise N-methyl-D-aspartate (NMDA)-mediated cortical input to the cerebellum. These fibres form increases in glutamate concentration in deep cere- glutamatergic synapses with the pontine nuclei in the bellar nuclei (Manto and Laute, 2008). The response brainstem. Cortical activity could thus be transmit- to alcohol and primidone in this patient is consistent ted to the cerebellar cortex via the mossy fibres and with involvement of the cerebellar micro-circuits in result in excessive stimulation of cerebellar granule EPC (figure 2) (Lisberger and Thach, 2013). This model and Purkinje cells (Lisberger and Thach, 2013). provides a possible explanation for EPC due to both Excessive glutamatergic stimulation of neurons in the cortical and subcortical pathology. deep cerebellar nuclei, analagous to that which occurs A cortical origin is demonstrated in most cases of EPC in ET, could then be transmitted from the cerebel- (Cockerell et al., 1996). As our patient experienced lum via the superior cerebellar peduncle (SCP). The generalised seizures and was demonstrated to have authors hypothesize that excitation is conveyed via the a transient discrete cortical T2 hyperintensity on pre- SCP to the thalamus, resulting in excessive stimulation sentation, we assume that the primary pathology at ventral anterior and ventral lateral thalamic nuclei.

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This hypothesis is consistent with studies indicating References thalamic involvement in EPC (Guerrini, 2009). In the present model, excessive activity is subse- Carta M, Mameli M, Valenzuela CF. Alcohol potently quently conveyed from thalamic nuclei to cerebral modulates climbing fiber-purkinje neuron synapses: role cortex. Interruption of such thalamo-cortical fibres, of metabotropic glutamate receptors. J Neurosci 2006; 26: in addition to cortico-pontine fibres described above, 1906-12. could thus result in EPC. This model therefore pro- Cockerell OC, Rothwell J, Thompson PD, Marsden CD, vides an explanation for EPC due to subcortical lesions Shorvon SD. Clinical and physiological features of epilep- (Juul-Jensen and Denny-Brown, 1966; Guerrini, 2009). sia partialis continua cases ascertained in the UK. Brain These observations suggest that further study of 1996; 119: 393-407. glutamatergic modulation may be beneficial for the treatment of EPC, which in general, is extremely diffi- Elble RJ. Tremor: clinical features, pathophysiology, and treat- cult to manage and often associated with considerable ment. Neurol Clin 2009; 27: 679-95.  functional disability. Frucht SJ, Bordelon Y, Houghton WH. Marked amelio- ration of alcohol-responsive posthypoxic myoclonus by Acknowledgements and disclosures. gamma-hydroxybutyric acid (xyrem). Movement Disord Jessica Rieckmann RN is acknowledged for her assistance in the 2005; 20: 745-51. clinical care of the patient. Ted Roberts MD FRCPC is acknow- ledged for recording the video material. Guerrini R. Physiology of epilepsia partialis continua and The case described was presented during the Meet the Experts subcortical mechanisms of . Epilepsia - Adults session at the 30th International Congress in 2009; 50: 7-9. June 2013. None of the authors have any conflict of interests to disclose. Juul-Jensen P, Denny-Brown D. Epilepsia partialis continua. Arch Neurol 1966; 15: 563-78. Legends for video sequences Lisberger SG, Thach WT. The cerebellum. In: Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ, eds. Rhythmic jerking of the right arm, recorded Principles of neural science. New York: McGraw-Hill, 2013: following the patient’s first generalised tonic-clonic 960-81. convulsion. The movements remained essentially continuous since presentation and were associated Manto M, Laute MA. A possible mechanism for the beneficial with major functional impairment of the use of the effect of ethanol in essential tremor. Eur J Neurol 2008; 15: right hand. 697-705. Key words for video research on Mostile G, Jankovic J. Alcohol in essential tremor and www.epilepticdisorders.com other movement disorders. Movement Disord 2010; 25: 2274-84. Syndrome: epilepsia partialis continua Etiology: lesion (unknown nature) Sinton CM, Krosser BI, Walton KD, Llinas RR. The effec- Phenomenology: motor seizure (simple) tiveness of different isomers of octanol as blockers of harmaline-induced tremor. Pflug Arch Eur J Phy 1989; 414: Localization: central (left) 31-6.

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