Lafora body disease: a case of progressive myoclonic epilepsy

Abstract

Progressive myoclonic epilepsy (PME) is a progressive neurological disorder. Unfortunately, until now, no definitive curative treatment exists; however, it is of utmost importance to identify patients with PME. The underlying aetiology can be pinpointed if methodological clinical evaluation is performed, followed by subsequent genetic testing. We report a case of PME that was diagnosed as Lafora body disease. This case emphasises that, suspecting and identifying PME is important so as to start appropriate treatment and reduce the probability of morbidity and prognosticate the family.

Background

Progressive myoclonic epilepsy (PME) is a neurological disorder characterised by myoclonus, seizures and increasing neurological dysfunction mainly in the form of dementia and ataxia.¹ Various diseases can present as PME, for example, Unverricht-Lundborg disease (ULD), Lafora body disease, myoclonic epilepsy with ragged red fibres (MERRF), type 1 sialidosis, neuronal ceroid lipofuscinosis (NCL) and Gaucher disease. One has to suspect PME, otherwise the diagnosis can be missed. Although no definitive curative treatment is available, it’s important to recognise PME for the following reasons: (1) Prognosis: diagnosis of PME will change the overall prognosis and the family has to be counselled accordingly. Some patients may be treated as juvenile myoclonic epilepsy, especially during the initial stages when cognitive decline is mild or absent. (2) Treatment: some drugs are to be avoided in patients with PME, as they may cause clinical worsening. (3) Workup for aetiology: clinically narrowing down the aetiological cause of PME is crucial so that focused genetic testing can be offered. Based on history, examination and electrophysiological findings, a plan can be drawn to investigate patients with PME.

Case presentation

An 18-year-old man presented with multiple seizures for the last 5 years. He started having myoclonic seizures that increased progressively, and over 6–7 months, he developed generalised tonic-clonic seizures (GTCS) that manifested one to two times/week initially. The latter subsequently increased to two to three seizures per day until the time the patient came to our institute. For the last 4 years, his scholastic performance has been poor until he was promoted to the ninth standard, and it has been over 1 year since he stopped going to school. For the last 3 years, he was not even able to manage his activities of daily living and would not ask about food and neither would he tell about bowel and bladder. He could recognise his parents and say ‘mama’ and ‘papa’ along with a few sentences constituting three to four words without any history of seeing bright coloured objects, formed images during seizures, weakness of body parts, and visual problems and deafness. He was started on different antiepileptics, including phenytoin with a maximum dose of 300 mg/day (6 mg/kg/day), clobazam 10 mg/day, carbamazepine (8 mg/kg/day) and sodium valproate with a dose 1000 mg/day (20 mg/kg/day) previously. However, his parents discontinued the medication because of no profound benefit in seizures. His elder sister died in adolescence after suffering from generalised seizures and myoclonic jerks for 6 years before her demise. On examination, his mini-mental state examination was 17/30, with both normal tone and deep tendon reflexes in all four limbs. Fundus and other cranial nerves examination were normal. Based on these features, the possibility of PME was considered. MRI brain and electroencephalography (EEG) were performed during the evaluation. EEG showed background slowing with multiple generalised as well as bilateral focal spikes and wave discharges. Moreover, the patient was unable to afford genetic testing. Differential diagnosis considered among aetiologies of PME is ULD or Lafora body disease. Axillary skin biopsy showed Lafora bodies (figure 1). He was treated with sodium valproate, levetiracetam and clobazam after which seizures decreased from two to three per day to one seizure after 3–4 days at 1-month follow-up.

Figure 1.

Axillary skin biopsy showed intracytoplasmic eosinophilic inclusions seen in eccrine glands and ducts suggestive of Lafora bodies.

Investigations

MRI brain performed at presentation was normal. EEG showed background slowing with multiple spikes and wave discharges. Axillary skin biopsy showed intracytoplasmic eosinophilic inclusions in eccrine glands and ducts, suggestive of Lafora bodies (figure 1).

Differential diagnosis: The following diseases are considered in the differential diagnosis of PME: ULD, Lafora body disease, MERRF, type 1 sialidosis, NCL and Gaucher disease. Final diagnosis of Lafora body disease was made by skin biopsy of the patient.

Treatment

The patient’s treatment was started with sodium valproate at 30 mg/kg, which was gradually increased to 50 mg/kg/day. Also, levetiracetam 30 mg/kg/day and clobazam 20 mg/day were administered that subsequently decreased seizures from two to three per day to one seizure after 3–4 days at 1-month follow-up.

Outcome and follow-up

Seizure occurrence frequency initially decreased from two to three per day to one seizure after 3–4 days at 1-month follow-up. However, his cognitive decline worsened and seizure frequency again increased to two to three episodes daily after 1 year, despite increasing antiepileptic dose. Parents were counselled regarding further workup and surgical options, including vagal nerve stimulation, but they could not afford the same due to financial constraints and he died 18 months post diagnosis.

Discussion

While evaluating a patient with myoclonic epilepsy, detailed family history, examination and electrophysiological findings are valuable in narrowing down differentials. First, benign myoclonic epilepsy syndromes must be differentiated from PME. Any patient with myoclonus, seizures and cognitive decline, decline in motor skills or ataxia should be suspected to have PME. ULD, Lafora body disease, MERRF, type 1 sialidosis, NCL and Gaucher disease commonly present as PME, as discussed above. Mode of inheritance is autosomal recessive for most PME aetiologies, except for MERRF having mitochondrial pattern of inheritance and adult-onset NCL (Kufs disease) having autosomal dominant variant.^{2 3} The age of onset also varies. Juvenile-onset NCL has earlier age of onset at around 4–7 years while adult-onset NCL has later age of onset at around 40 years.⁴ ULD occurs in late childhood, peaking at around 12–13 years, range is 8–15 years.^{5 6} MERFF and Gaucher disease have age of onset ranging from 10 to 40 years.^{2 7} Age of onset in Lafora disease is 8–19 years, peak age of onset is 14–16 years.⁸ Type 1 sialidosis symptoms appear in the second decade.⁹

Clinical features vary among the aetiological diseases. Focal occipital seizures are early manifestations in Lafora disease and generalised seizures occur soon after, action-sensitive and stimulus-sensitive myoclonus as well as absence, atonic and occipital seizures occur in Lafora disease. Neuropsychiatric manifestations are frequently present, followed by dementia, psychosis and cerebellar ataxia.^{10 11} In ULD myoclonus, GTCS typically occur at awakening or sometimes during sleep. Facial myoclonus may be present. Cascade seizures can occur with increasingly intense and violent myoclonic jerks, leading to a short GTCS. Major seizures are usually controlled, but myoclonus may persist despite treatment and may cause severe disability and inability to walk. Ataxia corresponds to the degree of myoclonus and improves if the latter is controlled. Cognitive impairment may be absent or vary from mild to moderate.^{5 6} MERRF usually presents with myoclonus as the first symptom followed by generalised epilepsy, ataxia, weakness and dementia. Proximal weakness is an important feature for identifying MERRF among PME cases.^{7 12} Juvenile-onset NCL presents with gradual onset of blindness followed by progressive cognitive decline over 3–5 years and behavioural disturbances, then seizures followed by extrapyramidal features. Characteristic dysarthria develops after the age of 10 years. Furthermore, cardiac conduction abnormalities may be present in older adults. Adult-onset NCL (Kufs disease) presents with ataxia, dementia, seizures and myoclonus, but no visual loss.^13–15In type 1 sialidosis, the first symptom is progressive loss of vision followed by nystagmus, cerebellar ataxia, myoclonus and GTCS. Myoclonus is progressive and stimulus-sensitive. Cherry-red spot is found on retinal examination in type 1 sialidosis.^{16 17} Gaucher’s disease presents as myoclonic seizures followed by intellectual deterioration, ataxia, trismus and tremor. On examination, characteristic horizontal gaze palsy is evident.^{17 18} Clinical features and genetics of PME aetiologies are tabulated in table 1. Some clinical clues to diagnosis of PME are given in table 2.

Table 1.

Clinical features and genetics of diseases presenting as progressive myoclonic epilepsy

Disease	Age of onset	Life span	Seizure types/ clinical features	EEG/ electrophysiology	Genetics
Juvenile-onset NCL	4–7 years	Death usually occurs in third decade	Gradual-onset blindness f/b cognitive decline then seizures f/b extrapyramidal features	Diffuse background slowing Generalised or less commonly focal spike and wave discharges Posterior spikes to low frequency photic stimulation	CLN3 gene mutation on chromosome 16p12 encoding lysosomal transmembrane protein
Adult-onset NCL	40 years	Normal life span	Ataxia, dementia, seizures, no vision loss	EEG changes as described above Giant VEP/SSEP can be seen	CLN4 gene on chromosome 20q13 encoding cysteine string protein
Lafora body disease	8–19 years	Usually after 10 years of disease onset	Focal occipital seizure f/b GTCS then dementia psychosis and cerebellar ataxia sets in	Background activity initially normal, then slows down as disease progresses Occipital discharges, generalised or focal paroxysmal activity Giant VEP/SSEP can be seen	EPM2A (Laforin dual specificity phosphatase) on chromosome 6p24 and EPM2B (Malin ubiquitin E3 ligase) on chromosome 6p22
Unverricht-Lundborg disease	Late childhood peaking at around 12–13 years	About 35–40 years	GTCS typically occur on awakening, facial myoclonus may be present	Background often moderately slow and tends to improve in later stages Photosensitivity present but tends to disappear after 10–15 years Giant VEP/SSEP can be seen	Cystatin B on chromosome 21, a cysteine protease inhibitor
MERRF	Ranging from 10 to 40 years	Variable	Myoclonus, epilepsy, ataxia, dementia, hearing loss, optic atrophy, neuropathy, proximal weakness	Slow background and generalised polyspike, spike and slow wave discharges	A to G substitution at nucleotide 8344 in mitochondrial DNA
Gaucher's disease type 3	10–40 years	Life expectancy of 20–40 years	Myoclonic seizures f/b intellectual deterioration, ataxia, trismus, horizontal gaze palsy	Multiple spike and sharp waves at frequency of 6–10/s, most prominent over posterior head region with diffuse spike wave complexes	Glucocerebrosidase deficiency due to mutations in glucocerebrosidase gene on chromosome 1
Type 1 sialidosis	Onset in second decade	Death usually occurs in third decade	Action-sensitive and stimulus-sensitive myoclonus, cherry-red spot on fundus examination	Low voltage and fast EEG background with bursts of bilateral spikes at frequency of 10–20 Hz	Lysosomal neuraminidase deficiency produced by gene located on chromosome 6p21

EEG, electroencephalography; GTCS, generalised tonic-clonic seizures; MERRF, myoclonic epilepsy with ragged red fibres; NCL, neuronal ceroid lipofuscinosis; SSEP, somatosensory evoked potential; VEP, visual evoked potential.

Table 2.

Clues to diagnosis

History/examination findings	Disease
Proximal weakness Hearing loss	MERRF
Horizontal gaze palsy	Gaucher disease
Cherry-red spot on eye examination	Type 1 sialidosis
Facial myoclonus, cascade seizures	ULD

MERRF, myoclonic epilepsy with ragged red fibres; ULD, Unverricht-Lundborg disease.

EEG shows slow background activity with focal or generalised spikes or spike and wave discharges. In fact, slow background activity in a patient with myoclonic epilepsy should raise the suspicion of PME. Also, giant visual evoked potential and somatosensory evoked potential can be seen in Lafora body disease, NCL and ULD.^19–21 Skin biopsy can help in identifying Lafora body disease and NCL. Characteristic periodic acid−Schiff-positive glycogen like intracellular inclusion bodies in myoepithelial cells of secretory acini of apocrine sweat glands and in eccrine and apocrine sweat duct cells are seen in axillary skin biopsy in Lafora body disease.²² In juvenile-onset NCL, eccrine glands show accumulation of products on skin biopsy. H&E stain shows round, eosinophilic inclusions. Electron microscopy shows fingerprint profile or mixed profiles (curvilinear, granular, fingerprint and rectilinear profiles).^{23 24} Muscle biopsy is helpful in MERRF where ragged red fibres are seen in 92% of patients.⁷

Drugs used to treat myoclonic seizures in PME are sodium valproate, clonazepam, phenobarbitone, levetiracetam, brivaracetam, zonisamide, topiramate and perampanel. Valproate should be avoided in mitochondrial cytopathies/MERRF. Carbamazepine, phenytoin and gabapentin should not be used in PME as they are known to worsen myoclonus. In fact, the widespread use of phenytoin was considered one of the major factors for adverse prognosis in ULD in earlier series as it worsens ataxia and seizures in ULD.^{17 25}

In conclusion, this case emphasises that methodological clinical approach to patients with PME not only helps in investigation, diagnosis and prognosis, but also in treatment by choosing appropriate antiepileptics and by avoiding specific drugs, which can be detrimental in a particular disease (eg, phenytoin in ULD).

Learning points.

• Suspect progressive myoclonic epilepsy (PME) in patients with myoclonic epilepsy and neurological dysfunction. Diagnosis if missed can lead to inappropriate therapy and deterioration in clinical condition of the patient.

• Methodological clinical approach can narrow down differential diagnosis and appropriate genetic testing can be performed.

• Carbamazepine, phenytoin and gabapentin should not be used in patients with PME as these drugs worsen myoclonus and/or ataxia.