Neurological Manifestations of Mitochondrial Disease
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1 Neurological Manifestations of Mitochondrial Disease Russell P. Saneto, DO, PhD Children s Hospital & Regional Medical Center/University of Washington
2 Disclaimer I will be discussing off-label use for many different medications. Information is based on personal experience and case reports or small studies published in the literature. Disclosures: I am a lecturer for GlaxoSmithKline. I have served as a consultant for Abbott Labs and Ortho-McNeil.
3 My Background Clinically, I am a Pediatrician, Neurologist, and Epileptologist (DO and Fellowship). Medical School: Des Moines University. Residency and Fellowship: Cleveland Clinic. My early education was in human genetics and neurobiology (PhD and Fellowship). PhD: NIH Pre-Doctoral at University of Texas. NIH Post-Fellowship: UCLA. Jeanne Kempner Fellow: UCLA
4 My Background My approach based on: Wisdom from my teachers and mentors. Experience acquired along the way. Knowledge gleaned by my patients and their parents have been my major teacher.
5 Specific Aims Introduction Bioenergetic dysfunction in the central nervous system. Brain function and energy Nerve function Primary CNS Manifestations Learning disorders Motor functions Gross motor Fine motor Coordination
6 Specific Aims Epilepsy Syndromes EEG Treatments Epilepsy mimics Movement disorders Sleep Disorders Autonomic Failure and Gastrointestinal Dysmotility. Headache Stroke and Stroke-Like Events. Psychiatric Anxiety, depression, psychosis, hallucinations, coma, and behavior problems.
7 Introduction The Brain 2% of body weight 20% of body oxygen consumption Approximately 60% to 70% of body energy. Dependent on oxidative phosphorylation.
8 Introduction Mitochondria are intracellular organelles responsible for energy production. Found in all cell types with the exception of mature red blood cells. Up to 100s of mitochondria per cell. Those cells requiring more energy to function have the most mitochondria; neurons and muscle cells. Brain is composed of neurons and glial cells. Neurons mainly use glucose for energy. Therefore, the brain has a high energy demand and is particularly sensitive to abnormal energy production.
9 Introduction Neurons prefer glucose for their function. ATP needed to generate electrical signaling, i.e. nerve action potential. Electrical signal is transferred to chemical signals at the synapse (end of the axon) to either other neurons (in the brain) or neurons and muscle cells outside the brain (in the peripheral nervous system and musculoskeletal system). Electrical energy is made (transferred) into chemical signaling, Chemical signaling imparts specificity of one signal (neurotransmitter) to only the neurons that have a specific receptor for that neurotransmitter. This specificity allows selective communication between neurons and brain areas.
10 Introduction
11 Introduction Development During development more neurons send their axons to specific areas of function than are needed. Sprouting or sending out axons requires a lot of energy. As the specific function becomes more hard wired or entrained, the brain prunes away those axons (neurons) that are not needed. Those neurons that fire together stay together, others are pruned away. This is what we mean by developing eloquence. Pathways become hard-wired as excess neurons are pruned away and neurons becomes specialized for particular functions.
12 Introduction
13 Introduction Different parts of the brain have different energy needs. Vary during development. Functions vary depending on need (examples): Cognition Executive function Vision Motor function Fine motor > Gross motor Autonomic function Respiratory Cardiac GI (neuronal and muscle)
14 Developmental Delay First, it is not completely clear how delays in cognition and motor function occur. Many, if not most, with a mitochondrial disease have both cognitive and motor delays. It is likely the energy deficit causing decreased neuronal axonal sprouting, axonal growth, decreased/increased pruning, and excess cell death. Deficits are more pronounced in those regions that are most dependent on energy and/or more axonal inputs and outputs. Insults can exacerbate problems with cognition.
15 Patient Case 1: Patient was 8 years old and developed seizures. She was eventually diagnosed with a complex III disorder. She was placed on Topamax, which controlled her seizures. Known side effects of Topamax are word finding problems and slowing of processing speed.
16 Case 1: Patient drawing at age 7 years.
17 Case 1: Patient drawing at age 8 years
18 Case 1. She underwent neuropsychological testing when she was seizure-free on Topamax. Functional IQ was 85 Verbal IQ was 100; Performance IQ was 65. She had a greater than 30 point split on actual and performance verbal and non-verbal testing. I then switched her seizure medication from Topamax to Lamictal. We also added antioxidant treatment with coenzyme Q10, vitamin E and C, and carnitine.
19 Case 1 After the switch to Lamictal: Functional IQ, actual was 102, Verbal IQ was 118 and performance IQ was tested at 84. Verbal split between verbal IQ and performance IQ was 34 points. Non-verbal performance was abnormal with Difficulties in design memory etc. Recently, her design for a Christmas card won a local competition as was selected as one of the cards used for the last holiday season at our children s hospital.
20 Developmental Delay This case shows that a patient with mitochondrial disease can be very sensitive to medications. She is unusual, as most of the induced deficit could be reversed by altering her medication. We have some information that other patients responded similarly. We don t know if all patients will have similar responses. Cognitive changes are extremely common in many patients with mitochondrial disease.
21 Non-Verbal Performance We have performed neuropsychological testing on 25 children. Ages ranged from 5 20 years. Electron transport chain defects: N=17 Single and multiple complex defects Primary Coenzyme Q deficiencies: N=2 mtdna mutations: N=5 3700G>A, 3243A>G, mt DNA deletions (KSS) Nuclear DNA mutations: N=1 467A>T homogygote
22 Non-Verbal Performance The average difference between verbal IQ and performance IQ (Verbal > Performance): Mean: -19. Range: Larges difference seen: All patients had normal MRI scans of the brain. Primary coenzyme Q deficiencies -33 and -42 (brothers). MELAS: Kearns-Sayre: - 29 (normal MRI scan at the time testing). Only a single patient had a performance IQ > verbal IQ. She had a complex III and a heart transplant.
23 Motor Delay
24 Motor Delay The back part of the brain is responsible for tone, coordination (part of which is fine motor skills) and deep tendon reflexes. Cerebellum The cerebellum is a very high energy demanding system. Neuron connections with the motor part of the brain as well as the deep gray structures (basal ganglia). Many mitochondrial disease patients have difficulties with: hypotonia, un-coordination, and fine motor skill. This part of the brain is also responsible for ataxia (fine coordination with smooth movement as well as gait).
25 Fine motor skills
26 Fine motor skills There is a technique called functional MRI or otherwise known as fmri. This technique uses the same instrument as the MRI to locate the source of increased neuronal activity (which is seen by increased blood flow, BOLD signal, or as we know it, oxidative phosphorylation). Increased blood flow shows neuronal activity. The more activity, the more blood is needed as oxygen demand increases. One way of testing fine motor skill is to have the patient tap their finger during a fmri scan.
27 Patient from Case 1. Finger tapping
28 Finger tapping on fmri What we see here is that the red spots are areas of increased neuronal activity. We are beginning to find that patients with mitochondrial disease have increased areas of neuronal activity with motor activity. Larger area than seen in non-mitochondrial disease patients. You can also see that the motor strip for finger motor movement and the cerebellum are involved. Cerebellar activation larger than seen in non-mitochondrial disease patients.
29 Treatment Currently, we do not know of any medical treatment for cognitive delays in language or in motor skills. However, knowing that most mitochondrial patients possess a non-verbal learning disorder, we can modify how a patient is taught to maximize learning. Auditory learning is easier than reading. We have a long way to go in this area.
30 Epilepsy Epilepsy is defined by two or more unprovoked seizures. Seizures are transient clinical events that are the result of abnormal excessive electrical activity within a population of cerebral neurons. Clinical events are not always positive events such as repetitive motor movements or stiffening. Many seizures are characterized by negative phenomena such as loss of awareness or muscle tone.
31 Epilepsy Patients with mitochondrial disease may also have paroxysmal events or movements which may confuse the diagnosis. Behavioral tuning out or staring. Stereotypies, such as hand flapping or turning in circles. Dystonia or abnormal position of an extremity. All epileptic seizures arise from abnormal cerebral activity and abnormal electroencephalogram (EEG) changes. All patients with mitochondrial disease and suspected seizures need to have an EEG. Any new event thought to be seizures, there should be an EEG performed to try and evaluate the event.
32 Types of Epilepsy One of the reasons we do the EEG, MRI scan, and take a very detailed history concerning what the seizures look like (seizure semiology) is that we want to figure out if your child has a particular epilepsy syndrome. Helps us predict which seizure medications work the best to control seizures. Helps to predict long term seizure control. Helps to indicate if epilepsy surgery is an option. Helps to differentiate between epileptic seizures and involuntary movements.
33 Type of Epilepsy: Epilepsy Syndromes Infantile Spasms Consists of a specific EEG pattern called hypsarrhythmia, epileptic spasms, and developmental regression or stagnation. Most develop Infantile spasms in early infancy, 4 months to 1 year with the most frequent age of 6 months.
34 EEG Hypsarrhythmia Pattern
35 Seizures Epileptic Spasms Quick jerks that have a 0.5 sec to 1 sec sustained tonic component. Often will drop head, extend arms and legs with bending at the waist (most classic spasm description). Tend to occur in clusters of 2 50 with multiple clusters in a day. Natural history: usually begin between 4 months and 1 year of age. Median age is 6 months. Spasms will usually stop after 3 4 years.
36 Treatment The de facto standard of care: ACTH is considered first line Efficacy is 60% - 80% Lots of side effects Very expensive: $23,000 per vial, average 4 6 vial per treatment. We have found this works well to stop spasms and alter the EEG pattern. Other medications: Vigabatrin, Zonisamide, Topamax, Valproic Acid, Benzodiazepines, Ketogenic Diet New medication with possibilities: Ganaxolone
37 Mitochondrial Disease and Infantile Spasms In our series of patients with electron transport chain defects: 12/67 (18%) patients had infantile spasms. ACTH was used in 11 patients 9 responded to ACTH with seizure freedom. All 9 eventually developed seizures after ACTH was stopped. 2 patients did not respond to ACTH. 1 patient became and stayed seizure free on the ketogenic diet. 11/12 eventually developed other seizure types and continued to have seizures that were unresponsive to a variety of seizure medications, including the ketogenic diet.
38 SE-MISF Syndrome The most common epilepsy syndrome in patients with electron transport chain defects is SE-MISF syndrome. Severe Epilepsy with Mulitfocal Independent Spike Foci (SE-MISF). Initially described by Noriega-Sanchez and Markand (1976). Electroclinical syndrome-meaning that it is base on the EEG pattern and clinical seizures. Looked at 108 patients Intellectual and neurological deficits. Many etiologies: CNS infections, Trauma, Hypoxia, Malformations of cortical development, gene defects (SCN1A).
39 SE-MISF Syndrome Literature suggests that highest incidence is between 4 7 years. But seen in age range from 2 months to 47 years. Multiple seizure types: Spasms, atypical absence, myoclonic jerks, and short tonic seizures. Most patients are intractable to seizure medications. Majority of patients are developmentally delayed or mentally retarded.
40 SE-MISF Syndrome Mitochondrial Disease: 42/67 patients with electron transport chain defects and seizures had this syndrome. Includes 11/12 patients with Infantile Spasms that later developed this syndrome. Single or multiple electron transport chain complexes were dysfunctional. Most common complex abnormality was complex III. Median age of seizure presentation was 3 years.
41 SE-MISF Syndrome: EEG
42 SE-MISF Syndrome:EEG
43 SE-MISF Syndrome: Seizures Seizure types: Atypical Absence: Staring with unresponsiveness. Epileptic Spasms: As with Infantile Spasms. Myoclonic Seizures: Quick jerks of the whole body, one side of the body, or one limb. Short Tonic Seizures: Stiffening for a short time, usually 2 20 seconds. May show some cyanosis around the lips. Non-specific motor seizures: Abnormal rhythmic or stiffening of a limb or a part of a limb.
44 SE-MISF Syndrome: Treatment Treatment is unsatisfactory: Most patients are on 3 or more seizure medications. Medication have helped reduce seizure frequency, but not seizure freedom. Several are on the ketogenic diet with some efficacy but no patient in our series is seizure free. 1/8 patients have become seizure free on the diet. 5 Patients (<12 years) had the VNS placed and no patients had a benefit. (Arthur et al., 2007) All 5 had multiple seizure types without benefit in any of the seizure types. We have a total of 10 patients, none of them have had a response from VNS placement. Hopeful of the medication Ganaxolone coming to market.
45 PE-MISF Syndrome Milder epilepsy with mainly focal or partial seizures (Partial Epilepsy with Multifocal Independent Spike Foci: PE-MISF). The EEG is similar to SE-MISF. However, these patients has seizures that are easier to control. Seizures are usually atypical absence or nonspecific motor seizures.
46 PE-MISF Syndrome: Mitochondrial Disease In our series: 8/67 patients with PE-MISF. Most common patient has a complex I defect. 5/8 have a complex I defect. Treatment is more optimistic with many seizure free. 6 are seizure free on one or two medications. Lamictal, Lamictal + Keppra, Zonisamide, Clobazam. 2 patient have infrequent seizures, < 1 month. Lamictal, Keppra, Valproic acid (use with caution).
47 Generalized Epilepsy The EEG shows generalized discharges. Generalized Epilepsy Syndromes Childhood absence, Juvenile Myoclonic Epilepsy, Generalized tonic clonic upon awaking, etc. Seizure types: Typical Absence, atypical absence, generalized tonic clonic, tonic, clonic, and myoclonic.
48 Generalized Epilepsy: EEG
49 Generalized Epilepsy: Mitochondrial Disease In our series of patients with electron transport chain defects): 12/67 had generalized discharges. Most common was complex I defect (4/12). Seizures: Atypical absence, myoclonic, tonic, and epileptic spasms. Seizure control is problematic as with SE-MISF. 9/12 continue to have seizures on multiple seizure medications. 3 patients in control are on Valproic acid, Zonisamide, Lamictal, Clobazam.
50 Generalized Epilepsy: Mitochondrial Disease Classic mitochondrial syndrome due to mitochondrial DNA mutation at 8344 (80%). Myoclonus epilepsy with ragged-red fibers (MERRF). Normal development with seizures developing from 3 years to adulthood. Myoclonic seizures and myoclonia. Intractable seizures with progressive cognitive decline. Muscle biopsy shows ragged-red fibers.
51 Epilepsy and Mitochondrial Disease Thoughts and Conclusions Approximately 50% of children with electron transport chain defects have seizures. Why only 50%? Infants with electron transport chain defects can present with Infantile spasms. Most children with electron transport chain defects and seizures: SE-MISF syndrome is the most common in our series. Unfortunately, treatment remains unsatisfactory.
52 Epilepsy Mimics and Involuntary Movements Few things in neurology have repetitive movements. Seizures Involuntary movements Dystonia, Athetosis, Chorea Tics Stereotypies Tremor
53 Epilepsy Mimics and Involuntary Movements To investigate: Home video the movement Video-EEG EEG MRI To avoid: Seizure medications when the repetitive movements are not seizures. Exceptions may be tics (Topamax), Dystonia or other basal ganglia induced movements (Carbamazepine or Keppra)
54 Valproic Acid Very important seizure medication, as it helps to control both generalized and partial seizures. However, its use in mitochondrial disease should be monitored with extreme caution. Valproic acid has been shown to induce/accelerate liver failure in patients with Alpers (POLG mutations). Valproic acid has been shown to cause reversible brain atrophy and encephalopathy in small numbers of patients with mtdna mutations.
55 Sleep Sleep is absolutely required but we really don t know why. When your son/daughter don t sleep, you don t sleep either. Is this true? Yep at least at my house. Sleep problems Getting to sleep. Staying asleep. Poor oxygenation during sleep.
56 Sleep Sleep problems associated with ADHD, increased seizures, headache, personality changes, obesity and behavioral problems. There are sleep centers within the brain (brainstem) that are often affected as part of the pathology of the mitochondrial disease. Sleep studies can be helpful to diagnosis possible sleep disorders and validate treatment efficacy.
57 Sleep Treatments Difficulty getting to sleep: Sleep hygiene (in all patients). Strict sleep schedule, no lights in room, etc. Medications: My preference in order- Melatonin Rozerem Clonidine Risperidal Trazadone (benzodiazepines, i.e. ambien are only short term solution and I have not found they work well).
58 Sleep Treatments Difficulty in staying asleep: medications in order of preference- Time released melatonin Rozerem Sending to grandparents house. There isn t much out there for staying asleep. However, there are some medications in clinical trials that may help answer this question.
59 Sleep Treatments Restless leg syndrome Gabapentin (neurontin) Tegretol Requip
60 Sleep Treatments Some sleep disorders are actually seizures. Video-EEG for diagnosis is often necessary. Differential: Sleep paroxysmal events Vs seizures Head banging Sleep walking Night terrors REM behaviors Suggestion that night time behaviors are seizures: Multiple events a night Events occur at various times during sleep
61 Autonomic Failure and GI Dysmotility Symptoms: Failure to thrive Severe reflux Vomiting (cyclic and/or non-cyclic) Severe constipation Severe diarrhea Pseudo-obstruction
62 Autonomic Failure and GI Dysmotility Treatments (individualize) Medications for reflux Mitochondrial vitamins Formula changes Elemental formula Alteration of choices of foods Formulas (Pedisure and others) to add to regular diet. Alteration of routes of intake NG G-tube Combinations (G-tube feeding at night) Timing of feedings Increased meals Night time feeds Continuous feeding
63 Autonomic Failure and GI Dysmotility Increasing calories May or may not help. Vary formulas with higher number of calories per once. Adding MCT oil 1 tbs = 50 kcals TPN (feeding via IV line) IVIg for pseudo-obstruction
64 Headache: Migraine Migraine Migraine without aura Migraine with aura Treatment Triggers should be avoided, headache diary helps. Always think about sleep apnea or night time hypoventilation. If infrequent Periactin if young (< 6yrs) Ibuprofen Ibuprofen + Benadryl Neurontin Tryptan (> 12 years)
65 Headache: Migraine Migraine If frequent Riboflavin mg before bed. CoQ mg If very frequent Youngster: Periactin (up to 4 mg qid) Amitroptyline (up to 2/mg/kg per day) Do ECG to check for long QTc Neurontin I stay away from beta-blockers and calcium channel blockers.
66 Headache: Migraine Migraine Variants Confusional migraine Hemiparesis or aphasic (can t talk) Cyclic vomiting Must differentiate from fatty oxidation problem, electron transport chain defect, cholesterol metabolic defect, mitochondrial DNA mutation, nuclear mitochondrial gene defect (i.e. POLG mutations).
67 Transient Encephalopathy Migraine variant or distinct entity? Patient who every fall has a 1 2 month period where she will become encephalopathic. Complex I defect Patient who every 3 4 months becomes encephalopathic. For 1 2 weeks becomes encephalopathic Currently unclear etiology, working him up for possible mitochondrial disorder.
68 Stroke and Stroke-like Events Fine line between complicated migraine, stroke and seizure, especially in MELAS. New onset seizure EEG If focal then MRI New onset of migraine Consider MRI New onset neurological abnormality MRI
69 Stroke and Stroke-like Events Often if the MRI shows new onset stroke, hospitalization is necessary.
70 Stroke and Stroke-like Events Treatment: Not from a vascular source (i.e. artery). Treatments for usual stroke etiologies not appropriate for most mitochondrial patients, such as tpa. For most mitochondrial patients: IV hydration IV carnitine (maybe) Supportive care Many patients present with seizures or headache EEG MRI Some case reports suggest that L-arginine may be helpful to prevent further strokes in MELAS.
71 Psychiatric Problems Accurate diagnosis is the initial best step Diagnosis is confirmed then usual psychiatric treatment is likely best. However, let me present a case where thinking outside the box was helpful.
72 Case Patient is currently a 16-year old boy with history of early onset seizures, episodic hemiplegia, global developmental delay and long standing behavioral problems of aggression, acting out, and austic like behavior. Recently admitted to the pediatric psychiatric ward for increasing agitation and behavioral outburst. Consulted as question of seizures causing behavioral outburst. EEG was performed. No events recorded, EEG was abnormal showing spikes but not seizures.
73 Case We decided to recheck his endocrine system. His TSH was low as well as T4. Currently further investigating. His FSH is elevated as well as testosterone levels. Talking with the psychiatrists, we think that his aggressive behavior as well as acting out (hitting, biting, etc) may be related to his elevated testosterone level. It is not obvious to us why his pituitary axis has changed. Mitochondrial dysfunction? His mitochondrial disease is not clear, abnormal mitochondrial numbers and morphology on muscle biopsy. His ETC was not revealing. He has some abnormal biochemistries suggestive of a mitochondrial disease. Just began to give him testosterone reducing medications.
74 Conclusions Many different neurological manifestations of mitochondrial disease. Standard diagnostic testing encouraged early in the disease course and may need to be repeated often. Many conditions have no standard treatments. Uncertainty for parents, patients as well as physicians. Begin with usual treatment for the symptom. Work with your local mitochondrial expert as well as your family/pediatrician/internist. As a group, we need to pool our experiences to begin to develop treatment strategies for varying types of mitochondrial disease.
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