Unverricht-Lundborg disease

C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Originally released November 11, 1996; last updated January 30, 2017; expires January 30, 2020

This article includes discussion of Unverricht-Lundborg disease, Baltic myoclonic epilepsy, Baltic myoclonus, Baltic myoclonus epilepsy, EPM1, Mediterranean myoclonic epilepsy, Mediterranean myoclonus, progressive myoclonic epilepsy 1, Unverricht disease, and Unverricht-Lundborg syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations

Overview

Unverricht-Lundborg disease (EPM1) is an autosomal recessive progressive myoclonus disease caused by mutations in the cystatin B (CSTB) gene mapped to chromosome 21q22.3. Most patients are homozygous for the expanded dodecamer repeat mutation alleles, but a few other EPM1-associated mutations have also been identified. Unverricht-Lundborg disease is characterized by recurrent stimulus-sensitive myoclonic and generalized tonic-clonic seizures and mild slowly progressive ataxia. Myoclonic seizures are severe and continuous and tend to be triggered by movement, stress, and sensory stimuli. The age of onset is between 9 and 13 years, and the condition is relatively frequent in the Baltic region, especially Finland, and Mediterranean countries. In this update, the author details developments in molecular genetics and improvement of pharmacological treatments of Unverricht-Lundborg disease. An important aspect of management is to avoid use of contraindicated antiepileptic drugs, such as phenytoin, carbamazepine, gabapentin, lamotrigine, pregabalin, tiagabine, or vigabatrin. Of the newer antiepileptic drugs, levetiracetam, zonisamide, and probably topiramate are the first choice of treatment, often in combination with valproate, clonazepam, clobazam, and piracetam.

Key points

 

• Unverricht-Lundborg disease (EPM1) is an autosomal recessive progressive myoclonic epilepsy.

 

• It manifests with stimulus-sensitive myoclonic jerks, generalized tonic-clonic seizures, slowly progressive ataxia, and mild intellectual dysfunction. Myoclonic seizures, the main disabling symptoms, are severe and continuous and tend to be triggered by movement, stress, and sensory stimuli.

 

• It is caused mainly by homozygous dodecamer repeat extension mutation in the cystatin B (CSTB) gene mapped to chromosome 21q22.3. Thus, the diagnosis can be confirmed by appropriate molecular genetic testing.

 

• Valproate, clonazepam, clobazam, piracetam, and, more recently, levetiracetam, zonisamide, and topiramate are the main antiepileptic agents. Nearly all other antiepileptic drugs are contraindicated.

Historical note and terminology

Heinrich Unverricht was a German physician, born on September 18, 1853, in Breslau; he died on April 22, 1912, in Magdeburg.

Image: Dr. Heinrich Unverricht
He was Professor of Medicine in Dorpat, now Tartu, Estonia. In 1891 he described a family of Baltic German origin in which several siblings suffered from a progressive neurologic disease with prominent myoclonus and generalized seizures. Tremor and rigidity have not been described in his patients (Puschmann 2009). He also published a volume named Die Myoclonie (Unverricht 1891).

Lundborg, from 1898 to 1910, compiled information on 17 patients afflicted by what is now known as Unverricht-Lundborg disease. They all belonged to 1 extensive kindred, the "Lister" family in Listerlandet of southern Sweden. He and Blekinge traced the affected family back to the 1700s (Lundborg 1901; Lundborg 1903; Lundborg 1912). Lundborg's thesis on “Die progressive Myoklonus-Epilepsie (Unverricht's Myoklonie)” was 1 of the earliest descriptions of recessive inheritance (Lundborg 1903). He had published the names of those affected, and he had concluded that the family had degenerated because of “unwise marriages.” Subsequently, marriage of relatives was carefully avoided in the group and no more cases occurred. According to Puschmann, Lundborg distinguished 3 stages of the disorder: Stage 1 began in childhood or early adolescence and consisted of nocturnal attacks of involuntary symmetric muscle twitches, which often were painful, caused anxiety, and reminded Lundborg of clonic, tonic-clonic, or tetanic seizures (Puschmann 2009). Patients were awake and conscious during the attacks. Stage 2 appeared a few years later with diurnal tremor, myokymia, and myoclonic or dystonic muscle contractions. Typically, the contractions initially affected the upper extremities symmetrically and subsequently involved lower extremities, head, neck, and finally, all voluntary muscles. Tactile and auditory stimuli elicited and stress aggravated these involuntary muscle contractions. Symptom severity fluctuated markedly from day to day. Gradually, increased muscle tone was noted in the interval between attacks. Stage 3 appeared several years to some decades later with disappearance of the nocturnal attacks while daytime muscle contractions became more and more pronounced. Regularly, marked generalized rigidity developed, leaving some patients utterly stiffened in certain poses, incapable of any voluntary movements. Lundborg noted that the clinical picture of some of his patients in the terminal phase reminded him of Parkinson disease.

Herman Bernhard Lundborg was a Swedish physician, born on April 7, 1868, in Vase, Varmlands lan, and he died in 1943. His radical racist ideas and his influence of Nazi ideology and acts overshadow his contribution to medicine. He was extremely negative to Jewish people and strongly involved in the ideology of racial hygiene. He was also responsible for the massive mapping, The Racial Character of the Swedish Nation, from 1926. He characterized 15% of patients in his work as morally or socially inferior (alcoholic, criminal, wanton, of bad character) and another 9.5% as psychiatrically inferior. He had served as a Professor for Racial Hygiene and he advocated the ideology of race biology. His influence contributed to the implementation of forced sterilization programs in Sweden and his view was that "The future belongs to the racially fine people" (Lundborg 1931).

Over the next 80 years, there was a great deal of discussion and misunderstanding of the nature and classification of the progressive myoclonic epilepsies (Berkovic et al 1986; Chan et al 2005; Genton et al 2005a; Genton et al 2005b; Shahwan et al 2005; Lohi et al 2006; Panayiotopoulos 2010; Berkovic 2008; Kalviainen et al 2008; Puschmann 2009), which had a number of causes, of which Unverricht-Lundborg disease is the most common. Advances in molecular biology have identified Unverricht-Lundborg disease as a specific genetic disorder encountered in many populations and parts of the globe. It has been described under different names, including Baltic myoclonus or Mediterranean myoclonus, before their identification by genetic studies as the same disorder as Unverricht-Lundborg disease. Similarly, Ramsay Hunt syndrome or dyssynergia cerebellaris myoclonica is no longer considered to be a separate disease (Andermann et al 1989; Harding 1989; Marsden et al 1990).

An excellent source of information is an online review of Unverricht-Lundborg disease by Lehesjoki and Kalviainen (Lehesjoki and Kalviainen 2016) and other updates (Kalviainen and Mervaala 2010; Crespel et al 2016).

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