SEARCH

SEARCH BY CITATION

Keywords:

  • Lafora disease;
  • Myoclonic progressive epilepsy;
  • Visual agnosia;
  • FDG-PET scan;
  • Occipital lobe;
  • Myoclonus

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results: Case Reports
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Establishing an early diagnosis of Lafora disease (LD) is often challenging. We describe two cases of LD presenting as myoclonus and tonic–clonic seizures, initially suggesting idiopathic generalized epilepsy. The subsequent course of the disease was characterized by drug-resistant myoclonic epilepsy, cognitive decline, and visual symptoms, which oriented the diagnosis toward progressive myoclonic epilepsy and, more specifically, LD. Early in the evolution in the first case, and before histopathologic and genetic confirmation of LD in both cases, [18]Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed posterior hypometabolism, consistent with the well-known posterior impairment in this disease. This suggests that FDG-PET could help to differentiate LD in early stages from other progressive myoclonic epilepsies, but confirmation is required by a longitudinal study of FDG-PET in progressive myoclonic epilepsy.

Lafora disease (LD) is a progressive myoclonic epilepsy (PME) with recessive autosomal transmission. LD starts in late childhood or adolescence with generalized epileptic seizures in patients without previous medical history. The clinical evolution is characterized by the association of generalized seizures (myoclonus, tonic–clonic seizures, absence, and atonic seizures), evocative occipital seizures and visual symptoms, and progressive cognitive impairment (Roger et al., 1983). Diagnosis is based on the detection of pathognomonic Lafora bodies [periodic acid–Schiff (PAS) inclusions] composed of polyglucosans, in skin biopsies, and on genetic testing: More than 90% of patients have mutations in the EPM2A or EPM2B gene, which codes for the proteins malin and laforin, respectively. These mutations interfere with normal glycogen metabolism. The purpose of this report is to describe the pattern of cerebral glucose metabolism as assessed by [18]Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in two patients with LD before histopathologic and genetic confirmation. We discuss FDG-PET contribution to early etiologic orientation in PME.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results: Case Reports
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Brain FDG-PET was performed according to the European Association of Nuclear Medicine procedure guidelines (Bartenstein et al., 2002). Integrated PET and computed tomography (CT) images were recorded during the interictal state, using hybrid PET/CT systems: a Biograph camera in Nancy (Siemens, Knoxville, TN, U.S.A.), and a Discovery ST camera in Marseille (GE Health Care, Waukesha, WI, U.S.A.). An activity of 150 MBq of FDG was injected intravenously into the patients, who were asked to rest in a quiet environment with eyes closed under clinical monitoring during the 30-min uptake period. No seizure was observed during the uptake period. The CT was recorded first for providing the attenuation-correction map and it was immediately followed by the three-dimensional (3D) PET recording. FDG-PET images were reconstructed, displayed with 3.0 × 3.0 × 3.0 mm3 voxels, and analyzed visually by an experienced nuclear medicine physician. Repeated electroencephalography (EEG) studies were performed during the whole course of the disease and within 2 days before the FDG-PET scan but not during the FDG uptake.

Results: Case Reports

  1. Top of page
  2. Summary
  3. Methods
  4. Results: Case Reports
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Patient 1

A 14-year-old girl with an unremarkable personal and familial history was referred to our unit for medically intractable generalized tonic–clonic seizures and myoclonus. Her medical history was characterized by normal development, except for frequent unexplained falls during early childhood, which worsened at the age of 12 years, simultaneously with a decline in school performance. Generalized seizures and absences appeared the following year. EEG showed well-organized background activity and spontaneous generalized but irregular spike-and-wave discharges sometimes triggered by intermittent photic stimulation (IPS). Epilepsy was initially well controlled with anticonvulsants and consistent with juvenile myoclonic epilepsy (JME). The initial diagnosis of idiopathic generalized epilepsy was challenged at the age of 14 years, when a school performance decline and distal myoclonus appeared. She was then referred to our epilepsy unit. On admission, neurologic and psychometric evaluations showed diffuse myoclonus, predominating in the extremities and exaggerated by action, static ataxia, executive dysfunction, and depression. EEG revealed slow background activity with discharge of generalized polyspikes and spike waves (Fig. 1A) and photosensitivity. Visual evoked potentials showed delayed and giant P100. Cranial magnetic resonance imaging (MRI) was unremarkable. FDG-PET scan revealed mild occipital hypometabolism (Fig. 1B). The axillary skin biopsy was first interpreted as normal and was sent to an expert laboratory for confirmation. Later the same year, the first visual symptoms appeared and were characterized by opsoclonus and phosphenes. Finally, the second interpretation of the biopsy reported pathognomonic PAS+ Lafora bodies. Molecular genetic analysis exhibited a compound heterozygous state for EPM2B (missense mutation and deletion).

image

Figure 1.   Patient 1 (A) Bipolar longitudinal electroencephalography (EEG) performed 3 days before [18]Fluorodeoxyglucose positron emission tomography (FDG-PET) and showing bursts of generalized polyspikes and polyspike-waves and slow background activity. (B) Axial FDG-PET scan showing bilateral posterior heterogeneous metabolism (white arrows).

Download figure to PowerPoint

Patient 2

A 13-year-old girl without previous remarkable medical history began epilepsy at the age of 11 years with tonic–clonic seizures. Initial EEG showed well-organized background activity with spontaneous generalized spike-and-wave discharges. Epilepsy was initially well controlled with anticonvulsants. Two years later erratic myoclonic jerks occurred. The patient also reported paroxysmal visual elementary hallucinations (brilliant flashes). EEG showed slow background activity and polyspike-waves that were either spontaneous or triggered by intermittent photic stimulation (Fig. 2A). Brain MRI was normal. At the same time her general state deteriorated associated with cognitive decline and resistance to various treatments. FDG-PET scan revealed bilateral posterior hypometabolism within the occipital lobes (Fig. 2B). Neuropsychological testing confirmed fast cognitive decline and detected visual agnosia. Despite the failure of skin biopsy to show Lafora bodies, the diagnosis of LD was ultimately established by electroclinical features and consistent genetic abnormality (homozygous missense mutation in the EPM2A gene).

image

Figure 2.   Patient 2 (A) Bipolar longitudinal electroencephalography (EEG) performed within 2 days before [18]Fluorodeoxyglucose positron emission tomography (FDG-PET) showing bursts of generalized polyspikes and slow background activity. (B) Axial FDG-PET scan showing more pronounced bilateral posterior hypometabolism (white arrows).

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results: Case Reports
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

This report describes two cases of LD with bilateral posterior PET hypometabolism consistent with occipital impairment. Early visual symptoms are characteristic of LD and manifest as paroxysmal elementary or complex visual symptoms, and also as constant deficits such as visual agnosia (Roger et al., 1983). They are reported in only 25–50% of cases of LD. Their transient and heterogeneous semiologic character can make them difficult to identify, especially in children. In our first case, the occipital impairment was initially clinically silent and was first revealed by the FDG-PET scan. In the second case, the PET scan was performed later and revealed a pattern of more pronounced posterior hypometabolism, possibly correlating with the more severe visual impairment and longer duration of LD. Diffuse metabolic changes involving especially frontal and occipital cortices have been shown in a recent MRI study (Villanueva et al., 2006). The physiopathology of these metabolic impairments remains unknown. Postmortem studies have shown that Lafora bodies are found predominantly in the thalamus, substantia nigra, cerebellum, and brainstem, and in lesser numbers in the frontal and occipital cortices (Striano et al., 2008). However, this reflects the accumulation of Lafora bodies over the whole course of the disease and does not provide any clues about their distribution earlier in the disease process (Van Heycop & DeJager, 1963).

There have been a few reports of FDG-PET scans in LD. One, concerning a 16-year-old Japanese boy, showed diffusely decreased glucose metabolism, particularly in the cerebellum (Kato et al., 1999). Another reported the case of an 18-year-old man with LD whose PET scan showed reduced glucose metabolism without topologic characteristics (Tsuda et al., 1995). In our two cases, PET scans reinforced our suspicion of LD (among other possible etiologies of progressive myoclonic epilepsy) because they revealed posterior hypometabolism consistent with early occipital impairment, which is characteristic of the disease.

In other types of progressive myoclonic epilepsy, FDG-PET scans have revealed abnormal glucose metabolism in the occipital regions of patients with various mitochondrial disorders including mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (Molnár et al., 2000) and in cases of juvenile neuronal ceroid lipofuscinosis (CLN3). In the latter case, PET scans revealed hypometabolism spreading from the calcarine to anterior areas. In other cases, the pattern of hypometabolism was clearly distinct: In a 23-year-old woman with Unverricht-Lundborg disease, PET scans showed only mild hypometabolism in the cerebellar hemispheres (Kondo et al., 2009). In two children with early onset Huntington’s disease, scans showed hypometabolism in the caudae nuclei (De Volder et al., 1988). In CLN2 (late infantile neuronal ceroid lipofuscinosis), hypometabolism was generalized in the cortical and subcortical regions (Philippart et al., 1997). The pattern of posterior hypometabolism in progressive myoclonic epilepsy may help to orient the etiologic diagnosis, which may be difficult in the early stage of the disease (Striano et al., 2008). The link between hypometabolism and the biochemical mechanism of the disease is currently unknown.

In most cases, electroclinical, histopathologic, and genetic confirmation of the diagnosis of LD takes several months. During this period of uncertainty, FDG-PET scans may provide additional evidence pointing toward the diagnosis of LD, but further evidence and a prospective longitudinal study of FDG-PET in PME are required.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results: Case Reports
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

We thank the reviewers for their helpful comments to the earlier versions of the manuscript.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results: Case Reports
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results: Case Reports
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  • Bartenstein P, Asenbaum S, Catafau A, Halldin C, Pilowski L, Pupi A, Tatsch K. (2002) European Association of Nuclear Medicine. European Association of Nuclear Medicine procedure guidelines for brain imaging using [(18)F]FDG. Eur J Nucl Med Mol Imaging 29:4348.
  • De Volder A, Bol A, Michel C, Cogneau M, Evrard P, Lyon G, Goffinet AM. (1988) Brain glucose utilization in childhood Huntington’s disease studied with positron emission tomography (PET). Brain Dev 10:4750.
  • Kato Z, Yasuda K, Ishii K, Takagi H, Mizuno S, Shimozawa N, Kondo N. (1999) Glucose metabolism evaluated by positron emission tomography in Lafora disease. Pediatr Int 41:689692.
  • Kondo T, Yamakado H, Kawamata J, Tomimoto H, Hitomi T, Takahashi R, Ikeda A. (2009) Unverricht-Lundborg disease manifesting tremulous myoclonus with rare convulsive seizures: a case report. Rinsho Shinkeigaku 49:4347.
  • Molnár MJ, Valikovics A, Molnár S, Trón L, Diószeghy P, Mechler F, Gulyás B. (2000) Cerebral blood flow and glucose metabolism in mitochondrial disorders. Neurology 55:544548.
  • Philippart M, Da Silva E, Chugani HT. (1997) The value of positron emission tomography in the diagnosis and monitoring of late infantile and juvenile lipopigment storage disorders (so-called Batten or neuronal ceroid lipofuscinoses). Neuropediatrics 28:7476.
  • Roger J, Pellissier JF, Bureau M, Dravet C, Revol M, Tinuper P. (1983) Early diagnosis of Lafora disease. Significance of paroxysmal visual manifestations and contribution of skin biopsy. Rev Neurol 139:115124.
  • Striano P, Zara F, Turnbull J, Girard JM, Ackerley CA, Cervasio M, De Rosa G, Del Basso-De Caro ML, Striano S, Minassian BA. (2008) Typical progression of myoclonic epilepsy of the Lafora type: a case report. Nat Clin Pract Neurol 4:106111.
  • Tsuda H, Katsumi Y, Nakamura M, Ikeda A, Fukuyama H, Kimura J, Shibasaki H. (1995) Cerebral blood flow and metabolism in Lafora disease. Clin. Neurol 35:175179.
  • Van Heycop THM, DeJager H. (1963) Progressive myoclonus epilepsy with Lafora bodies. Clinico-pathological features. Epilepsia 4:95119.
  • Villanueva V, Alvarez-Linera J, Gomez-Garre P, Gutierrez J, Serratosa JM. (2006) MRI volumetry and proton MR spectroscopy of the brain in Lafora disease. Epilepsia 47:788792.