Low-Frequency Photoparoxysmal Response in Adults

ORIGINAL RESEARCH

Low-Frequency Photoparoxysmal Response in Adults: An Early Clue to Diagnosis Julie Guellerin,* Sophie Hamelin,† Cecile Sabourdy,*† and Laurent Vercueil*†

Summary: Intermittent photic stimulation is performed during an EEG to evoke photoparoxysmal response. When they appear triggered by lowfrequency stimulation in children, they are suggestive of rare diagnosis, that is, neuronal ceroid lipofuscinosis. Among adults, their significance is less well understood. Low-frequency (,5 Hz) intermittent photic stimulation was performed over a period of 5 years during adult standard EEG. This retrospective study included all patients exhibiting low-frequency photoparoxysmal response. Five cases were identified. Three of them presented with active epilepsy (two progressive myoclonus epilepsy, one unclassifiable), two had visual deficiency, and three had dementia. The etiologies were MELAS (two), Creutzfeldt–Jakob disease (one), Kufs disease (one), and remained undetermined for one patient. In all patients, low-frequency photoparoxysmal response was observed years or months before the final diagnoses have been reached. Low-frequency photoparoxysmal response, classically associated with childhood progressive myoclonus epilepsy, seems to have a wider etiological spectrum in adult population. Moreover, this neurophysiological feature could be present before the final diagnosis in most cases. Systematically testing low frequencies during intermittent photic stimulation even during adult EEG seems warranted, particularly in a context of severe progressive neurologic deterioration. Key Words: Photosensitivity, Low frequency, MELAS, Creutzfeldt–Jakob disease, Kufs disease. (J Clin Neurophysiol 2012;29: 160–164)

P

hotosensitivity is defined as abnormal EEG activity induced by visual stimuli (Kasteleijn–Nolst Trenité et al., 2001). In photosensitive patients, intermittent photic stimulation (IPS) induces epileptiform discharges in the occipital cortex that may propagate to more rostral areas. Different classifications of EEG response to IPS have been proposed. One of them is from Kasteleijn–Nolst Trenité et al. (2001): grade I: photic following (or photic driving); grade II: orbitofrontal photomyoclonus; grade III: posterior stimulus-dependent response; grade IV: posterior stimulus-independent response; grade V: generalized photoparoxysmal response (PPR); and grade VI: activation of preexisting epileptogenic area. Grade III to V are commonly known as PPR and include the four types of the classification of Waltz et al. (1992). It has been proposed that photosensitivity may originate from an increased excitability of the occipital cortex (Parra et al., 2003; Siniatchkin et al., 2007). Usually, photosensitivity is observed at frequencies varying from 10 to 30 Hz. Using stimulation frequencies below 5 Hz, photosensitivity is very unusual, but in children, it may

From the *EFSN, Grenoble University Hospital, Grenoble, France; and †INSERM U836, Grenoble Institute of Neuroscience, Grenoble, France. Address correspondence and reprint requests to Julie Guellerin; e-mail: jguellerin@ yahoo.fr. Copyright Ó 2012 by the American Clinical Neurophysiology Society

ISSN: 0736-0258/12/2902-0160

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provide clues to diagnosis, especially in patients with progressive myoclonus epilepsy [neuronal ceroid lipofuscinosis (Binelli et al., 2000), Lafora disease (Roger et al., 1983), and mitochondrial disease (Canafoglia et al., 2001)]. Little is known about its diagnostic value in adults, despite occasional reports (Gourfinkel–An et al., 2007). In this study, we report on the occurrence of low-frequency PPR (LFPPR) in a consecutive series of five adult patients presenting with various diagnoses.

METHOD In the neurologic functional exploration unit at the Grenoble University Hospital, IPS, including low frequencies (1, 2, and 4 Hz), was systematically performed from 2003 to 2007 during adult standard EEGs. All patients with LFPPR, according to the following criteria, on at least one EEG recording were retrospectively included in this study. Clinical and electrophysiological data and etiologies were retrieved from medical charts. EEG recordings were reexamined to confirm the diagnosis. EEGs were recorded with scalp electrodes placed according to the international 10-20 system with both bipolar and referential montages (Deltamed, Bordeaux, France). All patients had undergone routine EEG usually lasting .20 minutes, including activating procedures (i.e., hyperventilation and IPS). The IPS was performed using a photostimulator (Deltamed or Braintronics; Almere, the Netherlands) with white flash. The flash lamp was placed 30 cm from the nasion. The IPS was performed using flash frequencies ranging from 1 to 50 Hz lasting 5 seconds after the closure of the eyes. The recordings were then reviewed to determine the background activity, the presence of spontaneous epileptiform discharges, and to characterize the PPR type, frequency, and location. Patients were considered for inclusion if IPS induced a paroxysmal EEG response according to the three following criteria: (1) time-locked response (starting with IPS), (2) generalized spikes or diffuse epileptiform discharges, and (3) IPS frequency lower than 5 Hz.

RESULTS Five patients (four women) were identified: the mean age was 37.4 years at the time of the LFPPR (range, 19–66 years). Three of the patients presented with active epilepsy (two progressive myoclonus epilepsies, one unclassifiable), two had visual deficiency, and three with severe and rapidly progressive dementia. Three patients had antiepileptic drugs. The clinical features and final diagnosis are described in Table 1. Brain MRI showed diffuse subcortical atrophy in two patients, and diffuse fluid-attenuated inversion recovery image showed uptake spreading cortically in one. The paraclinical findings are described in Table 2.

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Journal of Clinical Neurophysiology  Volume 29, Number 2, April 2012

TABLE 1.

Low-Frequency Photosensitivity

Clinical Features and Final Diagnosis

Patient Age, Number/Sex Years

Clinical Features

Sensory Impairment

1/M

66

Rapid impairment of cognition Visual hallucinations extrapyramidal syndrome Cognitive deterioration cerebellar Deafness syndrome neuropathy Myopathy lactic acidosis stroke Deafness

2/F

62

3/F

19

4/F

38

Frontal syndrome myoclonus gradual loss of autonomy

Optic retrobulbar neuritis

5/F

22

Impairment of psychomotor development beginning at 8 years of age

Blindness hearing impairment

Epilepsy

AED

Final Diagnosis

No

None

CJD

No

None

PME

MELAS (mutation ADN M A3243G) MELAS (mutation ADN M A3243G)

LTG 100 mg every day; CLB 5 mg 2 times per day PME VPA 1,000 mg 2 times Kufs disease (cerebral per day; CLZ 2 mg biopsy) 3 times per day Unclassified epilepsy LTG 150 mg every Unknown encephalopathy (atypical absence, day; VPA 350 mg tonic seizures) every day

PME, progressive myoclonus epilepsy; M, mitochondrial; AED, antiepileptic drugs; LTG, lamotrigine; CLB, clobazam; VPA, valproate; CLZ, clonazepam.

The PPR were induced by frequencies ranging 1 to 4 Hz (illustration on Figs. 1–5). Other EEG findings are described in Table 2. Final etiologies were mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS) (two patients), Creutzfeldt–Jakob disease (CJD), Kufs disease, and undetermined encephalopathy, each one case. In all but one case, LFPPR anticipated by months or years before the final diagnoses. The subsequent evolution of the response to IPS at low frequency was variable. In the patient with CJD (patient 1), LFPPR was present at the beginning of the disease but was lacking 8 months later. In patient 3 (MELAS), LFPPR was also lacking in the last available EEGs. In two patients (patients 2 and 5), only 1 EEG was performed.

DISCUSSION Visual sensitivity is observed in a substantial proportion of adult patients with epilepsy (Kasteleijn–Nolst Trenité et al., 2001). Photoparoxysmal response is a highly heritable electroencephalographic trait characterized by an abnormal cortical response to IPS. The pathophysiology is still mostly unknown, although photosensitivity has been recognized as a cortical phenomenon involving both visual pathways (parvo- and magnocellular) (Trenité, 2006). In

TABLE 2.

1 2

3 4

5

visual evoked potential (VEP) studies, patterns with a relatively low stimulus frequency and a high frequency were effective in uncovering cortical hyperexcitability in visually sensitive patients with idiopathic photosensitive occipital epilepsy, possibly because of the impairment in the contrast gain-control mechanisms, which are normally present at these temporal frequencies (Porciatti et al., 2000). Intermittent photic stimulation at low frequencies is useful in children because it can give clues to the diagnosis [neuronal ceroid lipofuscinosis (Binelli et al., 2000) or more rarely other progressive myoclonic epilepsies]. Low-frequency PPR has been less described in adults but can also provide a diagnostic orientation according to our study. However, low-frequency stimulation during IPS is not always a part of routine EEG, thus explaining the probable underreporting. However, in the past 10 years, IPS methods have been standardized (Kasteleijn–Nolst Trenité et al., 1999), and the recommended frequencies now range from 1 to 60 Hz. The present study reports on a series of five adults presenting with epilepsy, myoclonic features, or dementia who showed a PPR to low-frequency photic stimulation (LFPPR). Low-frequency PPR should be differentiated from photic driving (Kasteleijn–Nolst Trenité et al., 2001). Photic driving is represented by confluent VEPs to successive stimuli producing a regular EEG activity at the flash frequency, ending as soon as the

EEG, MRI, and CSF Characteristics Background EEG

IPS LF

MRI

CSF

1 Hz pseudoperiodic activity Well-organized background activity; sharp bifrontal waves with slow spikes in the posterior area Irregular background activity; spike waves associated with myoclonus Slow background activity; discharges of generalized spike waves located in the vertex 6 myoclonus Slow background activity; spreading rhythmic spikes

Spreading PPR at 1 and 2 Hz Spreading PPR at 1, 2, and 4 Hz

Diffuse FLAIR uptake spreading cortically Diffuse subcortical atrophy; diffuse leukoencephalopathy; calcification of the basal nuclei Lesions on the right cerebellar hemisphere

Protein 14.3.31 High CSF protein

Diffuse subcortical atrophy

N

Normal in 87

ND

PPR at 1 and 2 Hz 1 wide-spectrum photosensitivity PPR at 4 Hz 1 wide-spectrum photosensitivity PPR at 1 and 2 Hz

ND

FLAIR, fluid-attenuated inversion recovery image; LF, low frequency; CSF, cerebrospinal fluid; N, normal; ND, not determined.

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FIG. 3. IPS 1 Hz.

FIG. 1.

IPS 2 Hz.

stimulus train terminates. The location is predominantly posterior, and photic driving is considered a physiologic response. Moreover, photic driving is usually obtained at a frequency range from 5 to 30 Hz (Niedermeyer and Lopes da Silva, 1987). By contrast, LFPPR is a more diffuse response to IPS, spreading to the orbitofrontal regions, and the EEG pattern is an epileptiform discharge (spikes,

FIG. 2. 162

IPS 1 Hz.

polyspikes, and spike waves) that may continue after the stimulus ends. In the present study, we used criteria taking into account a threshold of 5 Hz (LFPPR as defined by a photic stimulation below 5 Hz) to prevent any confusion with photic driving. Moreover, diffusion to anterior region excluded driven VEP.

FIG. 4. IPS 4 Hz. Copyright Ó 2012 by the American Clinical Neurophysiology Society

Journal of Clinical Neurophysiology  Volume 29, Number 2, April 2012

FIG. 5.

IPS 2 Hz.

Low-frequency PPR in adults has been rarely reported. It was observed at the frequency of 1 Hz in a 32-year-old woman with progressive myoclonic epilepsy and frontal dementia starting at age 18 related to a S52R mutation of the neuroserpin gene (Gourfinkel– An et al., 2007). In CJD, a disease mainly affecting adults, the characteristic clinical features are progressive mental deterioration; behavioral abnormalities; and a deficit in higher cortical functions, visual disturbance, myoclonic jerks, and periodic, bilateral, synchronous, triphasic sharp waves on electroencephalography (de Seze et al., 1998). Giant VEPs have been reported in CJD, defined by amplitudes larger than 21 mV, in the early stage of the disease because of cortical hyperexcitability, and these are preferentially found in patients with myoclonus (de Seze et al., 1998). During flash stimulation at 1 Hz, Visani et al. (2005) observed the occurrence of large wave complexes that replaced spontaneous periodic sharp wave complexes. This phenomenon was present in nine CJD patients, eight of whom filled the criteria for giant VEPs (Visani et al., 2005). Giant VEPs may be explained by the loss of cortical inhibition as a result of diffuse neuronal dropout with consecutive hyperexcitability. In rare cases, such as ours, giant VEPs in CJD may lead to LFPPR. Neuronal ceroid lipofuscinosis is a progressive neurodegenerative disease occurring in infancy, which may also involve adults. Atypical forms of this disease have been described and are particularly represented in the late-infantile and juvenile-onset groups. Low-frequency PPR is characteristically reported with neuronal ceroid lipofuscinosis (Pampiglione and Harden, 1977). In an Indian study investigating patients with progressive myoclonus epilepsy, low-frequency photic stimulation evoked responses in 5 of 22 patients with neuronal ceroid lipofuscinosis (Sinha et al., 2007). The majority of reports on LFPPR concern childhood populations Copyright Ó 2012 by the American Clinical Neurophysiology Society

Low-Frequency Photosensitivity

(Binelli et al., 2000). In Kufs disease, only one adult case has been reported with LFPPR (Binelli et al., 2000). As far as we know, LFPPR was never described in adult patients with mitochondrial diseases, including MELAS. Thus, the present findings may extend the spectrum of diagnoses to be evoked when facing LFPPR in adults. Pathophysiology of LFPPR remains unknown. The LFPPR is characterized by a spread to anterior nonvisual cortical regions, suggesting that the propagation of the response is associated with an increased excitability extending beyond the occipital cortex (Siniatchkin et al., 2007). Indeed, giant somatosensory evoked potentials have also been reported to be associated with LFPPR in some cases such as neuroserpinopathy reports (Gourfinkel–An et al., 2007). The association between prominent spontaneous paroxysms in the EEG recordings and giant VEPs suggests that both are due to a common hyperexcitable change favoring neuronal synchronization. Interestingly, this neurophysiological characteristic was present before the final diagnosis in all but one of the present cases, suggesting that it may potentially contribute to an early diagnosis of a neurodegenerative disease. The underlying pathologic conditions in these patients included CJD (Heidenhain form) (Finsterer et al., 1999), MELAS (two cases), Kufs disease, and an undetermined severe but less progressive encephalopathy, all of which involve severe neurodegenerative processes. The significance of these data is limited by the low number of patients included in the study. A greater significance would require a larger number of subjects, but because such neurodegenerative disorders remain very rare, even a larger cohort would have been difficult to put together. Assuming that the presence of LFPPR would assist in the search for a diagnosis, a prospective study would provide a greater significance, but once again, rarity of either LFPPR or the investigated pathologic condition would need a very long time for recruitment.

CONCLUSION The LFPPR, classically associated with progressive myoclonus epilepsy in children, seems to have a wider etiological spectrum in the adult population because only two of the five patients studied presented this syndrome in the current study. These data underscore the relevance in systematically performing an IPS at low frequencies (below 5 Hz) in the setting of severe progressive neurologic deterioration. Moreover, if LFPPR is present, we advise investigating mitochondrial disease, Kufs disease, or CJD, depending on the clinical context. REFERENCES Binelli S, Canafoglia L, Panzica F, et al. Electroencephalographic features in a series of patients with neuronal ceroid lipofuscinoses. Neurol Sci 2000;21: S83–S87. Canafoglia L, Franceschetti S, Antozzi C, et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology 2001;56:1340–1346. Finsterer J, Bancher C, et Mamoli B. Giant visually-evoked potentials without myoclonus in the Heidenhain type of Creutzfeld-Jakob disease. J Neurol Sci 1999;167:73–75. Gourfinkel-An I, Duyckaerts C, Camuzat A, et al. Clinical and neuropathologic study of a French family with a mutation in the neuroserpin gene. Neurology 2007;69:79–83. Kasteleijn-Nolst Trenité DG, Binnie CD, Harding GF, Wilkins A. Photic stimulation: standardization of screening methods. Epilepsia 1999;40:75–79. Kasteleijn-Nolst Trenité DG, Guerrini R, Binnie CD, Genton P. Visual sensitivity and epilepsy: a proposed terminology and classification for clinical and EEG phenomenology. Epilepsia 2001;42:692–701. Niedermeyer E, Lopes da Silva F. Activation method. In: Electroencephalography: Basic principles, clinical applications and related fields. 2nd ed. Urban & Schwarzenberg, 1987:210–213.

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Pampiglione G, Harden A. So-called neuronal ceroid lipofuscinosis. Neurophysiological studies in 60 children. J Neurol Neurosurg Psychiatry 1977; 40:323–330. Parra J, Kalitzin SN, Iriarte J, et al. Gamma-band phase clustering and photosensitivity: is there an underlying mechanism common to photosensitive epilepsy and visual perception? Brain 2003;126:1164–1172. Porciatti V, Bonanni P, Fiorentini A, Guerrini R. Lack of cortical contrast gain control in human photosensitive epilepsy. Nature Neurosci 2000;3:259–263. Roger J, Pellissier JF, Bureau M, et al. Early diagnosis of Lafora disease. Significance of paroxysmal visual manifestations and contribution of skin biopsy. Rev Neurol (Paris) 1983;139:115–124. de Seze J, Hache JC, Vermersch P, et al. Creutzfeldt-Jakob disease: neurophysiologic visual impairments. Neurology 1998;51:962–967.

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Sinha S, Satishchandra P, Gayathri N, et al. Progressive myoclonic epilepsy: a clinical, electrophysiological and pathological study from South India. J Neurol Sci 2007;252:16–23. Siniatchkin M, Groppa S, Jerosch B, et al. Spreading photoparoxysmal EEG response is associated with an abnormal cortical excitability pattern. Brain 2007;130:78–87. Trenité DG. Photosensitivity, visually sensitive seizures and epilepsies. Epilepsy Res 2006;70:S269–S279. Visani E, Agazzi P, Scaioli F, et al. FVEPs in Creutzfeldt-Jacob disease: waveforms and interaction with the periodic EEG pattern assessed by single sweep analysis. Clin Neurophysiol 2005;116:895–904. Waltz S, Christen HJ, Doose H. The different patterns of the photoparoxysmal response; a genetic study. Electroencephalogr Clin Neurophysiol 1992; 83:138–145.

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