Case 8-2011: a 32-Year-Old Woman with Seizures and Cognitive Decline Katherine B

T h e new england journal o f medicine

case records of the massachusetts general hospital

Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 8-2011: A 32-Year-Old Woman with Seizures and Cognitive Decline Katherine B. Sims, M.D., Andrew J. Cole, M.D., Janet C. Sherman, Ph.D., Paul A. Caruso, M.D., and Matija Snuderl, M.D.

Presentation of Case

From the Departments of Neurology A 32-year-old woman was seen in the neurogenetics clinic at this hospital because (K.B.S., A.J.C., J.C.S.), Psychiatry (J.C.S.), of seizures and cognitive decline. Radiology (P.A.C.), and Pathology (M.S.), Massachusetts General Hospital; and the Absence seizures (staring spells) had reportedly begun when the patient was Departments of Neurology (K.B.S., A.J.C., approximately 5 years of age, and atonic seizures (sudden loss of muscle tone result- J.C.S.), Radiology (P.A.C.), and Pathology ing in dropping of the head and falling to the floor) had begun during adolescence. (M.S.), Harvard Medical School — both in Boston. She briefly received an unknown medication for atonic seizures in childhood. When she was in her mid-20s, she began to have frequent episodic tremors at rest that N Engl J Med 2011;364:1062-74. worsened with action, occasional ballistic (sudden and jerking) movement of the Copyright © 2011 Massachusetts Medical Society. arms, slowed speech, progressive difficulties with memory, and diminished reading comprehension, concentration, and sequence recall. At the age of 28 years, generalized tonic–clonic seizures lasting 1 to 15 minutes developed and increased in frequency, occasionally requiring hospitalization. Anticonvulsants were administered. When the patient was 29 years of age, after the onset of generalized seizures, 24-hour video electroencephalography (EEG) was performed at another institution. The results showed normal background and generalized high-voltage bursts of spike-wave and polyspike discharges at a rate of 3 per second. These discharges were more prominent with hyperventilation and photic stimulation, with a frequency of 1 to 2 per second. Her responses to a personality assessment inventory at that time were thought to indicate a high level of psychological distress and suggested an attempt to portray herself in a negative light; however, scores on scales that were sensitive to psychotic and paranoid thinking were more elevated than those on scales that were sensitive to depression, as is typically seen in a “cry for help” profile. When she was 31 years of age, neuropsychological testing showed weak- nesses in the domains of language, attention, executive functioning, and memory. No tests of mood or personality were administered. Cranial magnetic resonance imaging (MRI) without magnetic resonance spectroscopy was performed elsewhere 8 months before this evaluation and was reportedly normal. On the initial visit to the neurogenetics clinic, the patient was accompanied by a family member who assisted with the history. The patient had had increasing myoclonic seizures during the preceding weeks. She had normal early development

1062 n engl j med 364;11 nejm.org march 17, 2011 The New England Journal of Medicine Downloaded from nejm.org at HARVARD UNIVERSITY on September 7, 2011. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital and average academic performance, and she at- she returned to the neurogenetics clinic at regu- tended college but did not graduate. She reported lar intervals. She had headaches of increasing that she had a history of migraine headaches, frequency and progressive cognitive decline, with occasional shortness of breath, nausea, weight slower mentation and increasing difficulties with fluctuations, depression for which she had been short- and long-term memory. Despite the cogni- hospitalized, and a remote history of alcohol tive decline and extremely slow expressive lan- abuse. She lived with her partner of many years. guage and processing, she continued to have a She had taught art classes intermittently but was sense of humor. She had increasing seizure ac- currently receiving disability payments. Psycho- tivity, with generalized tonic–clonic and atonic active medications had included fluoxetine, seizures, myoclonus and ataxia, and episodes risperidone, olanzapine, and donepezil. Current of tremor. Her gait became shuffling, and de- medications included levetiracetam, lorazepam, creasing mobility and balance made her wheel- fluoxetine, zonisamide, phenobarbital, and olan- chair-dependent. She was hospitalized on several zapine, with zolpidem at night. She reported that occasions because of frequent and intractable she had smoked cigarettes heavily for 15 years, myoclonic seizures. Anticonvulsant medications drank alcohol rarely, and did not use illicit drugs. during that period included lamotrigine, pyridox- Her father had seizures that began at 30 years of ine, zonisamide, lorazepam, levetiracetam, pheno age, was hospitalized in a vegetative state for barbital, topiramate, donepezil hydrochloride, many years, and died at 48 years of age. Four of phenytoin, clobazam, and diazepam rectal gel. his siblings had intractable epilepsy, dementia, Smoking-cessation counseling was offered, but and early death. the patient declined. On examination, the patient was alert and Eighteen months after her initial evaluation, oriented, with a flushed face. The blood pressure cranial MRI revealed mild cerebral and cerebel- and pulse were normal. There were no dysmor- lar atrophy and mild periventricular hyperin- phic features, and the general physical examina- tensities on fluid-attenuated inversion recovery tion was normal, with no cutaneous pigmented images, with normal magnetic resonance spec- lesions, hepatosplenomegaly, or bone abnormali- troscopy and magnetic resonance perfusion. ties. On neurologic examination, she followed all Neuroophthalmologic examination showed no commands; she had slow, hesitant speech with abnormalities. Neurologic examination showed occasional paraphasic errors, decreased attention stuttering speech, marked cogwheel rigidity, de- and concentration, and deficits in short-term creased rapid alternating movements, and mild memory. Her ability to copy intersecting penta- dysmetria on finger-to-nose testing; no myoclo- gons was mildly impaired. She reported pain with nus was noted. An EEG was abnormal, showing eye movements; and horizontal movements were generalized background slowing during brief full, ocular pursuit movements were smooth, and wakefulness, as well as bifrontal spikes during refixation was normal. Vertical eye movements sleep, without associated clinical symptoms. There were not full, and no retinal abnormalities were were no electrographic seizures. noted. Visual acuity was normal. Motor move- One month later, while the patient was alone ments were initiated slowly. Tone was normal, and smoking, her shirt caught fire, and she sus- without dystonia. There was no focal motor weak- tained second- and third-degree burns to her ness, major sensory deficit, dysmetria, or ataxia. face, neck, chest, and shoulders, with an estimat There was no tremor; there were occasional ed 15% of the total body involved. She was taken myoclonic jerks but no atonic postural loss. No to another hospital, where intravenous fluids and overt seizures were noted. tetanus toxoid were administered, the trachea was Three months later, a skin biopsy was per- intubated, and mechanical ventilation was initi- formed; the pathological examination revealed no ated. She was transferred to this hospital, where evidence of lysosomal storage disease. The re- sedatives, anticonvulsants, glucocorticoids, mag- sults of selected genetic and metabolic tests were nesium, potassium, calcium, albumin, folate, thia- normal. mine, dalteparin, enteral nutrition, and inhaled During the next 18 months, the patient was ipratropium were administered. Topical wound followed by a neurologist near her home, and care was provided, and skin grafting was per-

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formed. Pneumonia due to methicillin-resistant chemia or intracranial hemorrhage and with post Staphylococcus aureus developed. On the 10th day, natal causes, including meningoencephalitis, in consultation with the family and her partner, postinfectious syndromes, cerebrovascular dis- and in accordance with the previously expressed ease, and hereditary degenerative disorders. In our wishes of the patient, comfort measures only patient, the Lennox–Gastaut Syndrome is exceed- were instituted. Mechanical ventilation was dis- ingly unlikely in view of the benign childhood continued, and the trachea was extubated. The course, normal neurodevelopmental history, and patient died shortly thereafter. absence of infectious, postinfectious, and vascu- An autopsy was performed. lar disease. Degenerative neurogenetic disorders, however, remain in the differential diagnosis. Differential Diagnosis With the onset of myoclonus in this patient’s teenage years and the background of relatively Dr. Katherine B. Sims: As the patient’s neurologist, I normal development and cognition, possible ab- am aware of the diagnosis. The patient had a sence seizures, and normal EEG findings, one normal birth and early neurodevelopmental his- might consider the juvenile myoclonic epilepsies tory. There was no history of central nervous sys- (OMIM number 254770), which account for 5 to tem infection, clinically significant head trauma, 25% of idiopathic epilepsies, with an onset be- childhood developmental regression, or deterio- tween 8 and 20 years of age7 (Table 1). The pa- ration under metabolic stress. tient’s history of a psychiatric or mood disorder The patient had a history suggestive of child- would not be incompatible with juvenile myo- hood absence epilepsy. Childhood absence epilepsy clonic epilepsies, which may occur with or with- (Online Mendelian Inheritance in Man [OMIM] out psychiatric features. However, the diagnosis number 600131) and juvenile absence epilepsy of juvenile myoclonic epilepsies is not supported (OMIM number 607631) are common idiopathic by her subsequent dementia, characterized by generalized epilepsies (OMIM number 600669).1,2 memory loss, aphasia, and generalized cognitive Distinguished by the age at onset, both child- slowing. Myoclonus or myoclonic seizures could hood absence epilepsy and juvenile absence epi- have been provoked by a variety of infections lepsy feature absence, early-morning, generalized (e.g., subacute sclerosing panencephalitis, Lyme tonic–clonic, and myoclonic seizures. A number disease, infection with the human immunodefi- of genes or susceptibility loci have been identi- ciency virus [HIV], Creutzfeldt–Jakob disease, and fied.3,4 Both childhood and juvenile absence epi- neurosyphilis), but in this patient there was no lepsies are relatively benign and usually remit- known history or exposure suggestive of infec- ting, although they can be a prelude to more tion, and the results of cerebrospinal fluid ex- progressive myoclonic epilepsy syndromes, as may amination were reportedly normal. be true in this case. Although it was not clear what contributing This patient’s history of falls and childhood role medications and psychosocial history had in seizures raises the possibility of atonic or myo- the patient's clinical history and examination, clonic astatic seizures or childhood epileptic en- the onset of generalized tonic–clonic seizures at cephalopathy.5 These epilepsies, often referred 28 years of age, as well as concern about wors- to as the Lennox–Gastaut syndrome,6 are char- ening cognitive function, caused us to consider acterized by the onset in childhood of atonic or the genetic progressive myoclonic epilepsies,8-10 myoclonic astatic seizures and usually have a especially those with an onset in youth or early poor prognosis. They characteristically occur adulthood. The long list of these disorders (Ta- during the period from infancy through 10 years ble 1) includes the late-onset form of Tay–Sachs of age, with neurodevelopmental failure. They disease (GM2 gangliosidosis), an autosomal reces- can be associated with a number of prenatal sive disorder characterized by psychiatric issues central nervous system diseases that result in and mild cognitive difficulties and a later onset maldevelopment, including primary cortical mal- of proximal weakness, ataxia, and seizures; juve- formations, tuberous sclerosis, congenital infec- nile Gaucher’s disease type IIIA, which is char- tions, and stroke. They also can be associated acteristically manifested as oculomotor ataxia, with perinatal causes such as hypoxia and is generalized tonic–clonic and myoclonic seizures,

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Table 1. Myoclonic Epilepsies.*

Disorder Subtype and Susceptibility Gene Locus and Chromosome MIM No. Juvenile myoclonic epilepsies EJM1 — EFHC1; EJM2 — 15q14; 254770 EJM5 — GABRA1; EJM3 — 6p21; EJM6 — CACNB4; EJM4 — 5q12-q14 EJM7 — GABRD; EJM8 — CLCN2 Progressive myoclonic epilepsies Storage disorders Gangliosidoses

GM2 (juvenile or late onset) HEXA 272800 Gaucher’s disease, type III (juvenile) GBA 231000 Neuronal ceroid lipofuscinosis Juvenile (Batten’s disease) CLN3 607042 Adult (Kufs’ disease autosomal recessive; Autosomal dominant: Parry type, autosomal dominant) 162350; autosomal recessive: 04300 Mucolipidosis Type I sialidosis (ML I, cherry-red-spot NEU 256550 myoclonus epilepsy) Galactosialidosis (juvenile or adult) PPCA 256540 Neuroaxonal dystrophy (adolescent or adult) NBIA2B 610217 Syndromes Autosomal recessive Unverricht–Lundborg disease EPM1, CTSB 254800 Progressive myoclonic epilepsy with ataxia EPM1B, PRICKLE1 612437 Lafora’s disease EPM2A, EPM2B; laforin 254780 Spastic paraplegia with myoclonus epilepsy 270805 Ataxia with myoclonic epilepsy and presenile 208700 dementia Myoclonus, ataxia, and deafness 159800 Autosomal dominant Dentatorubral-pallidoluysian atrophy ATN1 125370 Benign adult familial myoclonic epilepsy BAFME1 601068 Benign adult familial myoclonic epilepsy BAFME2 607876 Myoclonic epilepsy, Hartung type 159600 Myoclonus–dystonia DYT11, SGCE 159900 X-linked recessive (progressive myoclonic epi- 310370 lepsy with ataxia) Mitochondrial disorders Myoclonic epilepsy with ragged-red fibers 545000 Leigh’s disease 256000, 161700

* MIM denotes Mendelian Inheritance in Man.

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and late dementia; and Gaucher’s disease type wave discharges at 3 Hz, each lasting up to 10 IIIB and IIIC, in which adolescents typically have seconds. Discharges were activated by hyperven- mild neurologic difficulties without myoclonus. tilation, drowsiness, and photic stimulation. One Patients with Gaucher’s disease type IIIA may month later, after the patient received zonisamide also have non-neurologic manifestations, includ- at a dose of 200 mg per day, bursts of high- ing hepatosplenomegaly, anemia or thrombocy- amplitude 3-Hz delta were observed, but the topenia, infiltrative bone disease (which in types spike component had largely disappeared. Photic IIIB and IIIC systemic disease is more aggressive stimulation no longer elicited discharges. An EEG and severe), or all of these conditions. Progres- study performed at this hospital 2 years later, sive myoclonic epilepsy of the Unverricht–Lund- when the patient was 31 years of age, showed borg type and that associated with Lafora bodies slowing of the background posterior dominant as well as with sialidosis (cherry-red-spot myoc- rhythm, high-amplitude bursts of delta slowing lonus) would also be on the list of possible diag- every 5 to 15 seconds, and both unilateral and noses. In addition, one would have to consider bilateral epileptiform spike discharges arising the early-onset neurodegenerative disorders with from the anterior regions of the head every 30 to psychiatric features, including Niemann–Pick 60 seconds. A repeat study 3 weeks later showed type C disease, late-onset metachromatic leuko- more frequent and regular bursts of delta slow- dystrophy, juvenile Huntington’s disease, Wilson’s ing occurring every 4 to 7 seconds and with con- disease or juvenile Parkinson’s disease (parkin tinued focal and bilateral independent epileptic type), and the neuronal ceroid lipofuscinosis discharges intermingled. disorders — both the juvenile CLN3 form (Batten The paroxysmal slowing observed in this pa- disease)11 and the adult form (Kufs’ disease).12,13 tient is most frequently associated with diseases If we approach the differential diagnosis for affecting diencephalic and brain-stem structures, genetic juvenile or early-onset dementias with whereas the slowing of background rhythm epilepsy from the other end of the age spectrum, and the epileptic spikes are markers of cortical it would include Alzheimer’s disease (early-onset dysfunction. In patients with early progressive familial),14 Huntington’s disease-like 2, and the myoclonus epilepsies, the EEG may be indistin- multiple-system tauopathies (MAPT-related) with guishable from that in patients with common presenile dementia.15 These conditions include idiopathic, generalized epilepsy syndromes, with familial encephalopathy with neuroserpin inclu- normal background frequencies and bursts of sion bodies and the frontotemporal dementias well-formed 2.5- to 4-Hz spike-and-wave com- (Pick’s disease; frontotemporal dementia with par- plexes. As the illness progresses, generalized kinsonism; GRN-related frontotemporal dementia; slowing and loss of the posterior dominant inclusion-body myopathy with Paget’s disease, rhythm are seen in all the major diseases caus- frontotemporal dementia, or both; and CHMP2B- ing progressive myoclonus epilepsy.18 Patient’s related frontotemporal dementia (FTD-CHMP2B). with Kufs’ disease have photosensitivity, often at Of the MAPT-related disorders, only familial unusually low flash frequencies of 1 to 3 Hz, encephalopathy with neuroserpin inclusion bod- and an anterior predominance of epileptic dis- ies16 and frontotemporal dementia with parkin- charge, whereas patients with Lafora’s disease sonism17 have been associated with epilepsy. typically have occipital discharges. In this pa- At this point, Dr. Cole will review the EEG tient, the photosensitivity and anterior predomi- data, Dr. Caruso will present the neuroimaging nance of epileptic discharges was consistent with, findings, and Dr. Sherman will summarize the but not diagnostic of, Kufs’ disease. results of the neuropsychological testing, to clar- ify how these results might be helpful in estab- Neuroimaging Findings lishing a diagnosis. Dr. Paul A. Caruso: The MRI scan showed diffuse, largely symmetric, supratentorial and cerebellar EEG Findings atrophy. The frontal and parietal lobes along the Dr. Andrew J. Cole: Reports on two EEG studies per- high convexities and the superior vermis and cer- formed at another hospital when the patient ebellar hemispheres were most conspicuously in- was 29 years old were available. The first study volved (Fig. 1). The thalami showed normal sig- showed frequent bursts of generalized spike-and- nal and volume. There was no evidence of cortical

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A D

B E

C F

Figure 1. MRI Scans of the Brain from the Patient at 33 Years of Age and an Age-Matched Control.

A sagittal T1-weighted image (Panel A) and axial T2-weighted images at the level of the superior cerebellar hemispheres and vermis (Panel B) and the frontal and parietal lobes (Panel C) show largely symmetric atrophy in the brain of the patient. Atrophy involves the superior vermis and frontal and parietal lobes, as evidenced by abnormally wide sulci and cortical volume loss. Images of the brain of an age-matched control are shown in the same views (Panels D, E, and F).

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malformation, phakomatosis, sequelae of prior coding but preserved retention of information. TORCH infection (toxoplasmosis, other [syphilis, The patient also had a severely impaired ability varicella, parvovirus infection, HIV infection], to name pictured objects. rubella, cytomegalovirus infection, and herpes The patient’s combined psychiatric symptoms simplex virus infection), hypoxic–ischemic injury, and her specific cognitive findings are consistent stroke, meningoencephalitis, or granulomatous with a pattern of deficits associated with either disease. There were no findings to allow a di frontal or subcortical systems dysfunction. agnosis of an inborn error of metabolism or a Dr. Sims: Our patient had childhood absence disorder of myelin such as a gangliosidosis, mu- seizures, followed by the onset in her late 20s of colipidosis, mucopolysaccharidosis, or dentato- myoclonus, generalized seizure disorder, and de- rubral-pallidoluysian atrophy (DRPLA). Proton mentia. Generalized atrophy detected on MRI and magnetic resonance spectroscopy over the left abnormalities on EEG studies and neuropsycho- basal ganglia showed a slight decrease in levels logical testing suggested a subcortical dementia, of N-acetylaspartate. Decreased levels of N-acetyl and given the history of autosomal dominant aspartate may be seen in Unverricht–Lundborg transmission (Fig. 2), the autosomal recessive disease, Lafora’s disease, and neuronal ceroid lipo- disorders could be excluded. fuscinosis, but the findings were not specific for The differential diagnosis for the late-onset a particular neurodegenerative disorder. autosomal dominant myoclonic epilepsies with dementia excludes the majority of lysosomal dis- Results of Neuropsychological Testing orders, with the exception of rare cases of late- Dr. Janet C. Sherman: The patient underwent a neuro- onset autosomal dominant neuronal ceroid lipo- psychological assessment at another hospital at fuscinosis13,19-23 (Table 2). The neuropsychiatric the age of 31 years. She presented with memory features in this patient, even in the absence of a difficulties of several years’ duration. The onset history or evidence of multisystem dysfunction, and progression of her cognitive difficulties were would not necessarily rule out consideration of unclear, although psychiatric symptoms were a mitochondrial encephalopathy with ragged-red prominent feature of her clinical presentation. fibers, but one would expect maternal inheri- The patient reported extreme levels of psychiatric tance of that disorder. Leigh’s disease, a mito- distress, and an inventory that she completed at chondrial encephalopathy, can result from nu- a different outside hospital 1 year before this neu- clear DNA mutations but is usually an autosomal ropsychological evaluation showed psychotic and recessive disorder. It would be exceedingly rare paranoid thinking. for Leigh’s disease to develop in the fourth de- The neuropsychologist assessed the patient’s cade of life. Huntington’s disease might be con- functioning across a broad range of cognitive sidered, given the history of autosomal domi- domains on norm-referenced, standardized tests. nant familial, neuropsychiatric, and generalized She was generally cooperative during testing but myoclonic epilepsy; however, the patient did not occasionally declined to complete more difficult have the dystonia, rigidity, or chorea that typi- tasks. In contrast to her estimated range of pre- cally accompanies Huntington’s disease. morbid abilities from low average to average, her Severe, progressive myoclonic epilepsy would full-scale, verbal, and performance IQ scores were be rare in Huntington’s disease. Patients with borderline. Her most prominent areas of deficit benign adult familial myoclonic epilepsy type 1 were in measures of attention and executive func- and type 2 have tremors, and the disorder is non- tioning. She had difficulty on tests requiring progressive, making this diagnosis unlikely in working memory (e.g., digit sequence reversals our patient. The diagnosis of myoclonic epilepsy and mentally solving arithmetic problems), cog- of the Hartung type (without Lafora bodies) nitive flexibility (e.g., alternate sequencing of might be considered in this patient, but it is not numbers and letters in a visual test and complex rapidly progressive and thus unlikely. Although problem solving in which her rate of persevera- one cannot exclude X-linked disorders from con- tive responses was elevated), and strategic aspects sideration, these manifestations in a female pa- of memory. Specifically, her performance on tient would be exceedingly rare. Only a single memory tests was characterized by impaired en- family with X-linked progressive myoclonic epi-

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Affected

Probably affected ? ? Pathology results 1 2 I

Died, Died, 83 yr 25–30 yr “No known seizures”

1 2 3 4 5 6 7 II

Died, 48 yr Died, 81 yr Seizure onset, 39 yr

1 2 3 4 5 6 7 8 9 10 III

Died, 39 yr Seizures

Biopsy Biopsy Biopsy Autopsy Biopsy

6 IV 1 2 3 4 5 7 8 9

Died, 47 yr Died, 46 yr Died, 21 yr Died, 36 yr Died, 48 yr Early Early Seizure onset, Seizure Seizure Seizure onset, Seizure onset, seizures seizures 16 yr onset, 30 yr onset, 16 yr 30 yr early 20s Autopsy

1 2 3 3 4 5 6 V

Seizure Seizure Died, early 30s Born 1977 Born 1975 onset, onset, Seizure onset, Died 2009 13 yr 21 yr 13 yr “Schizophrenia”

1 VI

Figure 2. Family Pedigree. The family pedigree of the patient (indicated by the arrow) suggests autosomal dominant inheritance. Red dots indicate patients with pathological features (granular osmophilic deposits and fingerprint bodies) shown on biopsy to be consistent with neuronal ceroid lipofuscinosis. Squares indicate male family members, circles female family members, diamonds sex unknown, and slashes deceased family members who were affected or probably affected.

lepsy has been described, and that family had from patients with familial encephalopathy with prominent ataxia.24 The absence of a cherry-red neuroserpin inclusion bodies, the hallmark neu- spot on ophthalmologic examination would usu- roserpin inclusion bodies would be expected to ally rule out the diagnosis of sialidosis. Lafora’s be present in neurons. Patients with the Unver- disease would, by definition, be associated with richt–Lundborg type of progressive myoclonic periodic acid–Schiff (PAS)-positive cytoplasmic epilepsy would typically have a more protracted inclusions in biopsy specimens of skin, muscle, or course of dementia. other tissues. If biopsy specimens were obtained Biopsy and autopsy specimens obtained from

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Findings deposits posits, fingerprint in - fingerprint posits, curvilinear clusions, inclusions Electron-Microscopical Granular osmophilic Granular inclusions Fingerprint Granular osmophilic de - osmophilic Granular

Neuropathological Findings substantia nigra, midbrain, and cere - and midbrain, nigra, substantia bellum nigra, midbrain, cerebellum midbrain, nigra, storage loss; cell nigra substantia phy; thala - ganglia, basal cortical, the in nuclei cerebellar stem, brain mus, reticulata), and compacta (pars nigra striatum in binding D2-receptor of loss midbrain and pons, spinal cord spinal pons, and midbrain ) Reported in the Literature. the in Reported type ) Parry Disease, Storage in the hypothalamus, thalamus, hypothalamus, the in Storage Hypothalamus, thalamus, substantia thalamus, Hypothalamus, atro - cerebellar temporal, parietal, Frontal substantia the in loss neuronal Generalized Storage in the thalamus, substantia nigra, substantia thalamus, the in Storage

Clinical Features myoclonus, dementia, aphasia dementia, myoclonus, (chorei - dyskinesias onset), after yr 3 ataxia rigidity, form), disease Parkinson’s then pression disease Parkinson’s dementia, yr) 2–5 over (course and suprabulbar movements, midal dysfunction cerebellar Seizures, facial dyskinesia, dementia dyskinesia, facial Seizures, Weakness, incoordination, ataxia, incoordination, Weakness, (within dementia myoclonus, Seizures, de - or dementia, seizures, Myoclonus, seizures, ataxia, dysarthria, Myoclonus, extrapyra- issues, behavioral Dementia, Seizures, myoclonus, dementia, ataxia dementia, myoclonus, Seizures,

47 42 41–58 46–49 Alive at Alive publication Age at Death (mean or range, yr) range, or (mean 40 38 32 32–40 40–50 27–30 Onset Age at 2 3 4 5 6* 7 1 No. Family Cases of Autosomal Dominant, Late-Onset, Neuronal Ceroid Lipofuscinosis (Kufs’ Lipofuscinosis Ceroid Neuronal Late-Onset, Dominant, Autosomal of Cases 2. Table * This family was related to the patient under discussion.

1070 n engl j med 364;11 nejm.org march 17, 2011 The New England Journal of Medicine Downloaded from nejm.org at HARVARD UNIVERSITY on September 7, 2011. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital family members of this patient showed electron- ter. The basal ganglia and hippocampus were of microscopical inclusions (granular osmophilic normal size and shape. deposits and fingerprint bodies) suggestive of Microscopical examination showed a massive a neuronal ceroid lipofuscinosis.20 Families with accumulation of lipofuscin in virtually all neu- autosomal dominant or autosomal recessive dis- rons of the central nervous system (Fig. 3), includ- ease with the Kufs’ type of neuronal ceroid lipo- ing the cortex, subcortical structures, cerebellum, fuscinosis have been described, although reports brain stem, and spinal cord. The accumulated of families with autosomal dominant disease are material in neurons was PAS-positive and showed exceedingly rare (Table 2). Electron microscopy strong autofluorescence with a broad excitation of skin-biopsy specimens from this patient was and emission spectrum. Electron-microscopical performed three times, and all three samples studies revealed an accumulation of dense osmo- were negative. Enzyme testing to detect palmitoyl- philic material with a vague internal architecture protein thioesterase 1 (PPT1; CLN1) and tripeptidyl- resembling fingerprint shapes and occasional peptidase 1 (TPP1; CLN2), as well as molecular curvilinear bodies. There was some loss of neu- DNA testing for CLN3, CLN5, CLN6, CLN7, and rons in the substantia nigra pars compacta, locus CLN8 mutations, were negative. Without the fam- ceruleus, and cerebellar granule-cell layer, accom- ily history and electron-microscopical findings panied by reactive gliosis. in family members, we would have performed The white matter was relatively unaffected, more extended testing appropriate to this case with well-preserved myelin. There was mild as- and its differential diagnosis. These tests would trogliosis with some microglial activation. The have included liver-function studies, measure- normal brain weight, with no clinically signifi- ment of biochemical markers of oxidative- cant loss of neurons or secondary white-matter phosphorylation dysfunction in blood and mus- degeneration, suggested that the disease had not cle-biopsy specimens, and blood tests to detect reached its end stage.25 ceruloplasmin and lysosomal enzymes. We would General autopsy findings included an enlarged have performed molecular testing for Hunting- heart with biventricular hypertrophy and biatrial ton’s disease; mitochondrial encephalopathy dilatation but no clinically significant coronary with ragged-red fibers; DRPLA; PARK2; EPM1 artery disease. PAS, PAS with diastase, Luxol fast (Unverricht–Lundborg disease); and EMP2A (La- blue, and iron stains revealed modestly increased fora’s disease). We would also have performed levels of lipofuscin in the myocardium, which cholesterol-esterification studies and filipin stain- were confirmed on electron microscopy. ing in fibroblasts to detect Niemann–Pick disease In summary, the findings are diagnostic of type C. In addition, a brain biopsy might have adult-type neuronal ceroid lipofuscinosis, or Kufs’ been considered. disease. Dr. Sims: The autopsy findings confirmed the Dr. Katherine B. Sims’s clinical suspicion of late-onset neuronal ceroid Diagnosis lipofuscinosis (Kufs’ disease). Because the genes for the autosomal dominant and autosomal reces- Autosomal dominant lysosomal disorder, onset sive forms of Kufs’ disease have not been identi- in young adulthood, most likely neuronal ceroid fied, molecular testing was limited to the exclu- lipofuscinosis (Kufs’ disease). sion of known genetic loci of neuronal ceroid lipofuscinosis. Further genetic studies involving Pathological Discussion families with Kufs’ disease may in the future identify the cause of the disease, and fibroblasts Dr. Matija Snuderl: The brain weighed 1360 g (nor- from this patient are being used to model the mal weight, 1250 to 1400). The hemispheres were disease and to provide a resource for preclinical symmetric, and there was no evidence of trauma testing of possible therapeutic agents. Until we or herniation. Coronal sections of the brain re- have a better understanding of the basis of this vealed a preserved cortical band and a sharp disease, the treatment of myoclonic epilepsy with junction between gray and white matter, with no dementia will remain challenging, as it was in macroscopical defects in the gray or white mat- this patient.

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Cortex

White matter

B C D

E F G

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include avoiding potentially neurotoxic agents Figure 3 (facing page). Neuropathological Findings at Autopsy. such as phenytoin and avoiding drugs that may A low-magnification view of the cerebral cortex (Panel A, exacerbate generalized spike-and-wave discharg- Luxol fast blue–hematoxylin and eosin stain) shows a es such as carbamazepine, tiagabine, gabapentin, preserved cortical band and underlying white matter. pregabalin, and vigabatrin. Modest benefit has On higher magnification, white matter has preserved been reported or observed in some patients treat- myelinated tracts, whereas cortical neurons have an ed with valproate, lamotrigine, benzodiazepines accumulation of pale golden brown material (Panel A, insets). The accumulated lipofuscin in the cytoplasm (e.g., clonazepam), piracetam, levetiracetam, or of neurons (Panel B, Luxol fast blue–hematoxylin and zonisamide. No data are available regarding the eosin stain) is positive on periodic acid–Schiff staining role of lacosamide or rufinamide. (Panel C) and appears as dense osmophilic material with vague internal architecture on electron microscopy (Panel D). In tissue sections stained with nuclear 4’-6-diamidine- Anatomical Diagnosis 2-phenylidole dihydrochloride (DAPI), the accumulated material is strongly autofluorescent, with a broad exci- Kufs’ disease (autosomal dominant, Parry type, tation and emission spectrum (Panels E, F, and G). young-adult–onset neuronal ceroid lipofusci nosis).

This case was presented at the Neurology Grand Rounds, May Discussion of Management 13, 2010. Disclosure forms provided by the authors are available with Dr. Cole: The treatment of seizures in patients the full text of this article at NEJM.org. We thank Dr. Thomas Byrne for assistance in organizing the with progressive myoclonus epilepsies is unsatis- conference and the physicians at Berkshire Medical Center and factory. General principles of treatment should the family members for input on the case history.

References 1. Commission on Classification and and therapeutic aspects. J Neurol 2010; sity of Washington, 1993 (updated March Terminology of the International League 257:1612-9. 2010). Against Epilepsy. Proposal for revised 9. Ramachandran N, Girard JM, Turn- 16. Miranda E, MacLeod I, Davies MJ, et al. classification of epilepsies and epileptic bull J, Minassian BA. The autosomal re- The intracellular accumulation of poly- syndromes. Epilepsia 1989;30:389-99. cessively inherited progressive myoclonus meric neuroserpin explains the severity of 2. Beghi M, Beghi E, Cornaggia CM, epilepsies and their genes. Epilepsia 2009; the dementia FENIB. Hum Mol Genet Gobbi G. Idiopathic generalized epilep- 50:Suppl 5:29-36. 2008;17:1527-39. sies of adolescence. Epilepsia 2006;47: 10. Shahwan A, Farrell M, Delanty N. 17. Kertesz A. Pick’s complex and FTDP-17. Suppl 2:107-10. Progressive myoclonic epilepsies: a review Mov Disord 2003;18:Suppl 6:S57-S62. 3. Crunelli V, Leresche N. Childhood ab- of genetic and therapeutic aspects. Lancet 18. Berkovic SF, Andermann F, Carpenter sence epilepsy: genes, channels, neurons Neurol 2005;4:239-48. S, Wolfe LS. Progressive myoclonus epi- and networks. Nat Rev Neurosci 2002;3: 11. Mole SE, Williams RE. Neuronal ce- lepsies: specific causes and diagnosis. 371-82. roid lipofuscinoses. In: Pagon RA, Bird TC, N Engl J Med 1986;315:296-305. 4. Winawer MR, Rabinowitz D, Pedley Dolan CR, Stephens K, eds. GeneReviews 19. Boehme DH, Cottrell JC, Leonberg SC, TA, Hauser WA, Ottman R. Genetic influ- [Internet]. Seattle: University of Washing- Zeman W. A dominant form of neuronal ences on myoclonic and absence seizures. ton, 1993 (updated March 2010). ceroid-lipofuscinosis. Brain 1971;94:745- Neurology 2003;61:1576-81. 12. Jalanko A, Braulke T. Neuronal ceroid 60. 5. Zupanc ML. Clinical evaluation and lipofuscinoses. Biochim Biophys Acta 20. Burneo JG, Arnold T, Palmer CA, diagnosis of severe epilepsy syndromes of 2009;1793:697-709. Kuzniecky RI, Oh SJ, Faught E. Adult- early childhood. J Child Neurol 2009;24: 13. Josephson SA, Schmidt RE, Millsap P, onset neuronal ceroid lipofuscinosis (Kufs Suppl:6S-14S. McManus DQ, Morris JC. Autosomal dom- disease) with autosomal dominant inheri- 6. Arzimanoglou A, French J, Blume WT, inant Kufs’ disease: a cause of early onset tance in Alabama. Epilepsia 2003;44:841-6. et al. Lennox-Gastaut syndrome: a consen- dementia. J Neurol Sci 2001;188:51-60. 21. Ferrer I, Arbizu T, Peña J, Serra JP. sus approach on diagnosis, assessment, 14. Bird TD. Early onset familial Alzhei A Golgi and ultrastructural study of a management, and trial methodology. mer disease. In: Pagon RA, Bird TC, dominant form of Kufs’ disease. J Neurol Lancet Neurol 2009;8:82-93. Dolan CR, Stephens K, eds. GeneReviews 1980;222:183-90. 7. Zifkin B, Andermann E, Andermann [Internet]. Seattle: University of Washing- 22. Ivan CS, Saint-Hilaire MH, Christen F. Mechanisms, genetics, and pathogene- ton, 1993 (updated March 2010). sen TG, Milunsky JM. Adult-onset neuro- sis of juvenile myoclonic epilepsy. Curr 15. van Swieten JC, Rosso SM, Heutink P. nal ceroid lipofuscinosis type B in an Opin Neurol 2005;18:147-53. MAPT-related disorders. In: Pagon RA, African-American. Mov Disord 2005;20: 8. de Siqueira LF. Progressive myoclonic Bird TC, Dolan CR, Stephens K, eds. 752-4. epilepsies: review of clinical, molecular GeneReviews [Internet]. Seattle: Univer- 23. Nijssen PC, Brusse E, Leyten AC, Mar-

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tin JJ, Teepen JL, Roos RA. Autosomal 24. Wienker TF, von Reutern GM, Ropers SE. CLN4: adult NCL. In: Goebel HH, dominant adult neuronal ceroid lipofus- HH. Progressive myoclonus epilepsy: Mole SE, Lake BD, eds. The neuronal ce- cinosis: parkinsonism due to both striatal a variant with probable X-linked inheri- roid lipofuscinoses (Batten’s disease). and nigral dysfunction. Mov Disord 2002; tance. Hum Genet 1979;49:83-9. Amsterdam: IOS Press, 1999:77-90. 17:482-7. 25. Martin JJ, Gottlob I, Goebel HH, Mole Copyright © 2011 Massachusetts Medical Society.

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