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[A] OS 211: Integration, Coordination and Behavior Lec 11: Disorders of the Basal Ganglia December 5, 2013 Dr. Jamora, MD OUTLINE I. Basal Ganglia A. Anatomy B. Function II. Movement Disorders A. Approach of diagnosis B.Terminologies III. Athetosis IV. Chorea A. Huntington’s Disease V. Ballism VI. Dystonia A. Classification B. Types C. Neuroimaging D. Treatment E. Other Dystonias VII. Parkinsonism A. Parkinsonism-Plus Syndromes B. Heredo-degenerative Diseases C. Primary: Parkinson I. BASAL GANGLIA A. ANATOMY Represents massive subcortical nuclei derived from the telencephalon Corpus Striatum o Concerned with somatic motor function o Consists of two parts: Neostriatum (Caudate Nucleus and Putamen): receptive component of the basal ganglia Paleostriatum (Globus Pallidus [Interna and Externa lateral to it: putamen]): major outflow component of the basal ganglia More lateral to the externa is the putamen o Amygdaloid Nuclear Complex A component of the limbic system Oldest part of the basal ganglia (archistriatum) Concerned with visceral, endocrine, and behavioral functions Corpus striatum Striatum Caudate Nucleus Putamen Globus Pallidus Lentiform Nucleus Figure 1. Parts of Basal Ganglia B. FUNCTION To control and regulate the activities of the motor and the premotor cortical areas via various reverberating circuits so that voluntary movements can be performed smoothly Motor activity is intricately controlled by the interactions of 3 major regions of the brain: cortex, cerebellum, and basal ganglia These three regions influence the lower motor neurons either: o Directly via the pyramidal system Corticobulbar and corticospinal tracts o Indirectly via the extrapyramidal system Basal ganglia circuit Figure 1. Basal Ganglia Circuit Transer’s understanding: The basal ganglia is responsible for the fine tuning of motor activities, thus its general action is inhibitory (in order for it to regulate movement and facilitate motor control). The internal globus pallidus and substantia nigra pars reticulate have tonically active inhibitory neurons which inhibit the brainstem and the VA/VL thalamic nuclei. So for example, the person wants to move, the decision starts at the cortex, and the cortex will give a signal (glutamate) to the striatum (caudate and putamen), which activates either D1 or D2 receptors. The effect depends on the receptors stimulated. CHUA, COPE, CORALDE 1 If the D1 receptor is stimulated, the striatum will release GABA targeting the GPI and nigra reticulate, inhibiting its inhibitory action to the brainstem and thalamus. The thalamus will then send stimulatory signal to the cortex by releasing glutamate. So basically, stimulation of D1 receptor is stimulatory to the cortex, saying go na yang move na yan! Trivia: This is called the Direct Pathway. If the D2 receptor is stimulated, the striatum will release GABA enkephalin which inhibits the GP Externa (GPE). GPE normally inhibits the subthalamic nucleus (STN) by releasing GABA; however, since GPE is inhibited, less GABA is released. (Thus, D2 receptors inhibit the inhibitor of STN) Therefore, the subthalamic nucleus will not be inhibited, and it will release glutamate to excite the substantia nigra pars reticulate and GP interna to inhibit the brainstem and thalamus. Stimulation of D2 receptor is inhibitory to the cortex, saying, no sobra na yung excitatory signals, stop muna! Trivia: This is called the Indirect Pathway. Dopamine from the Nigra compacta is stimulatory since it stimulates D1 receptors and inhibits D2 receptors. Why is it important? Basically for hyperkinetic movement disorders there is a problem in dopamine. In Parkinsonism there is decrease dopamine so patient has slow movements. II. MOVEMENT DISORDERS Neurological syndromes in which there is either an excess of movement (hyperkinetic) or a paucity of voluntary & automatic movements, should be unrelated to weakness or spasticity (hypokinetic); thus a stroke patient is not hypokinetic What these seemingly different clinical disorders share is that the parts of the brain that are affected are part of the same system Almost all movement disorders stem from disturbances in the basal ganglia or their connections The basal ganglia control system is a damping or modulating system. Excess discharge in the basal ganglia produces slowing; a lack of discharge produces hyperactivity. Lesions in the striatum produce deficits in the ability to perform complex motor responses. A. APPROACH OF DIAGNOSIS (INVOLUNTARY MOVT DISORDER) Careful history Physical examination Ancillaries: o Thyroid function tests, RPR (for syphilis), LFTs (liver function tests) o Heavy metal screen o Urine/serum copper o Ceruloplasmin o Lumbar tap o Serum/ urine organic & AA (useful for pediatric cases) Ophthalmologic exam for Wilson’s disease(slit lamp)- for Kayser Flescher Rings Genetic testing (if available) Electrophysiological: o EEG, EMG, EP o ENG for nystagmus, PSG for sleep study Neuroimaging Neuropsychological testing Tissue biopsy B. TERMINOLOGIES Excess of movement o Hyperkinesia – excessive movement ▪ Akathisia (uncontrollable motor restlessness), ataxia (inability to coordinate voluntary motor movements), athetosis, ballism, chorea, dystonia, hyperekplexia, moving toes/fingers, periodic leg movements of sleep, myoclonus, dyskinesia, restless legs, tics, tremors o Dyskinesia – any unnatural movement still excessive Paucity of movement ○ Hypokinesia – decreased amplitude of movement ▪ Parkinsonism (most common), blocking tics, cataplexy and drop attacks; Catatonia, psychomotor depression, and obsessional Page 1 / 7 Lec 11: Disorders of Basal Ganglia OS 211 slowness (common psych patients); Apraxia, freezing phenomenon, hesitant gaits, hypothyroid slowness, rigidity, stiff muscles ○ Bradykinesia – slowness of movement ○ Akinesia – loss of movement III.ATHETOSIS Slow, writhing, continuous, involuntary movements , DISTAL Speed can sometimes be faster and blend with those of chorea (choreoathetosis) If not present in certain body parts at rest, it is brought out by having the patient do voluntary movement elsewhere on the body (overflow) Movements not sustained Very distal, piano-like movements Basic patterns of movement include: alteration between extensionpronation and flexion-supination of the arm and between flexion and extension of the fingers, the flexed and adducted thumb being trapped by the flexed fingers as the hand closes. Other characteristic movements are eversion-inversion of the foot, and alternate wrinkling and relaxation of the forehead or forceful opening and closing of the eyelids. Choreoathetosis – from distal to proximal IV. CHOREA Involuntary, irregular, purposeless, non-rhythmic, abrupt, rapid, unsustained movements of any part of the body due to overactivity of dopaminergic neurons 2016 trans: Proximal; Sir: Distal; Internet source: both proximal and distal:P Flows from one body part to another Grander (bigger movements compared to athetosis), more proximal, patient is usually unaware of the movements, described as nervous by the family Unpredictable in timing, direction, and distribution Partially suppressible and often incorporated into semi-purposeful movements – parakinesia Parakinesias: actions that attempt to hide the involuntary movement (e.g. putting hand on hip or inside pockets, fixing the hair) Accompanied by motor impersistence – inability to maintain a sustained contraction Seen in SLE (microinfarcts in the brain leading to chorea) and Huntington’s disease HYPERGLYCEMIA CAN CAUSE choreoathetosis A. HUNTINGTON’S DISEASE Prototype disease with chorea; problem in the indirect pathways Described by George Huntington in 1872; autosomal dominant disorder; onset in adult life Trinucleotide disease: mutation in the huntingtin gene in chromosome 4p16.3 (PATHOLOGY: excess of CAG repeats) ○ CAG repeats (9 -33) – unaffected ○ CAG repeats (34 -39) – intermediate ○ CAG repeats (> 40) – lead to Huntington’s Figure 2. Basal Ganglia Circuit of Hyperkinetic Movt Disorders So in Huntington’s disease, There is less GABA from the D2 receptors D2 receptors won’t release too much GABA so less inhibition on GPE GPE would then release too much GABA inhibiting the subthalamic nucleus Less glutamate will be released less excitation of IGP and Nigra reticulata Less GABA More stimulation of the cortex using glutamate by VA/VL thalamic nuclei thus more chorea form movements Table 1. Commonly used medications in Huntington’s disease. DOSE (INITIAL TO MAXIMUM SYMPTOMS MEDICATION RECOMMENDED) Haloperidol Chorea (antipsychotics) (anticipation): the more CAG repeats, the younger the onset Mean age of onset: 40 years (range: 2-75 years) 5% of patients had the first signs before age 20 (juvenile form) Mean duration of illness: 17-20 yrs max: of up to 45 years of age Main COD (cause of death): pneumonia by aspiration or choking, suicide and fall An incurable disease Triad of Huntington’s Disease: ○ Chorea ○ Dementia ○ Behavioral abnormalities (reason why patients consult psychiatry first before neurology) Marked atrophy and gliosis of the caudate nucleus (severely shrunken producing a marked dilatation of the lateral ventricle) and putamen Loss of indirect pathways results in hyperkinesia (chorea) Diffuse degenerative disease, with widespread loss of cholinergic and GABAergic neurons and secondary cerebral atrophy Luria test — test for executive dysfunction in Huntington’s disease o Patient cannot do the sequence: cognitive impairment CHUA, COPE, CORALDE 12.5 to 100 mg daily, in divided doses Reserpine 0.1 to 0.3 mg daily, in divided doses Diazepam Carbidopa/Levodopa Trihexyphenidyl Bromocriptine Sertraline Depression Fluoxetine Paroxetine Number of repeats inversely correlates with age at onset Tetrabenzene Clonazepam Bradykinesia, rigidity Risepridone Psychosis 0.5 to 30 mg daily Olanzapine Quetiapine 0.5 to 4 mg daily 1.25 to 20 mg daily 25/100. 1 tab QD to TID 1 mg BID to 5 mg TID 1.25 mg BID, increase as tolerated 25 to 200 mg daily 10 to 80 mg daily 10 to 60 mg daily 0.5 to 6 mg daily 2.5 to 20 mg daily 25 o 750 mg daily Treatment: based on symptoms ○ No cure: treat symptoms only, not the disease ○ Give antipsychotics for symptomatic relief ○ Haloperidol, clonazepam, diazepam, risperidone ○ Genetic counseling On neurological examination: ○ Bradykinesia ○ On Luria test, cannot do palm, edge first – for frontal lobe dysfunction V. BALLISM Greek word ‘ballein’, to throw Involuntary, irregular, large-amplitude flinging movement of the limbs with poor pattern More proximal involvement: leg and arm flexion My be severe to cause physical exhaustion or injury Most common cause of hemiballism: stroke Others: hypergylcemic hemiballism- diabetic, presentation was hemichorea, if we control the sugar, chorea will disappear Page 2 / 7 Lec 11: Disorders of Basal Ganglia Bilateral ballismus is very infrequent and usually asymmetrical. Nonketotic hyperosmolar coma is the usual cause. Hemiballism – one side of the body, lesion in the contralateral subthalamic nucleus (STN) or its connections, or to multiple small infarcts in the contralateral striatum Biballism – bilateral lacunes in the basal ganglia May also be caused by levodopa overdose Tend to fall due to the involuntary movements VI. DYSTONIA Twisting, patterned movements that tend to be sustained at the peak of the movement Frequently repetitive and often progress to prolonged abnormal postures Agonist and antagonist muscles co-contract (to and fro movements) Often initially brought out by voluntary movements (action dystonia) and can later become sustained and extend to other body regions (Harrison’s, 17th Ed.). Can be aggravated by stress and fatigue and attenuated by relaxation and sensory tricks such as touching the affected body part (Harrison’s, 17th Ed.). Responsive to sensory tricks or “geste antagoniste” e.g. when you have neck dystonia, if something touches the jaw there is reduced muscle contraction, thus some patients wear masks to reduce the dystonia There are at least 13 genetic loci for dystonia. Dystonia may occur as a part of neurodegenerative conditions such as Huntington's disease, Parkinson’s disease, Wilson's disease, corticobasal degeneration, progressive supranuclear palsy, the Lubag form of dystonia-parkinsonism (DYT3) found only in Filipinos, and mitochondrial encephalopathies. In contrast to the primary dystonias, dystonia is usually not the dominant neurologic feature in these conditions. A. CLASSIFICATION ACCORDING TO AGE OF ONSET Early (<26 years) ○ Tends to generalize ○ Starts from the leg or arm and progresses to the other limbs and trunk. Late (>26 years) ○ Tends to remain localized/focal ○ Neck, face, or arms OS 211 B. TYPES CERVICAL DYSTONIA (Focal) Abnormal head and neck posture – spasmodic torticollis Example of a focal dystonia Jerky movements of the head and intermittent or constant head deviation at rest; there is a “no-no tremor” as the patient tries to position his head in the midline 1.5 – 1.9 times more common in women Peak incidence is usually on the 5th decade Onset: 4th to 6th decade (70-90%) Deviations in any single plane or combinations of directions ○ Torticollis (neck turning) – ipsilateral SCM and contralateral splenius capitis and levator scapulae are involved ○ Anterocollis (neck flexion) – bilateral SCM ○ Retrocollis (neck extension) – bilateral splenius capitii and semispinalis capitii ○ Laterocollis (head tilt) – ipsilateral SCM, splenius capitis, and scalene ○ Or combination of any of the above Muscle contractions can be painful and associated with dystonic tremor and a secondary cervical radiculopathy. Treatment: Botulinum toxin injection costing Php 17 000 per vial (100 units), can last for 3-6 months Know the muscle to know where to inject the botulinum toxin BLEPHAROSPASM (Focal) Intermittent closure or sustained bilateral eyelid closure as a result of involuntary contractions of the orbicularis oculi muscles (very frequent eye blinking) A focal dystonia Patients would sometimes have to pry open their eyes to be able to see Mild spasms of the frontalis and the lower and middle facial muscles BSP (blepharospasm) + OMD (oromandibular dystonia) = Meige’s syndrome How is it different from tics? ○ Tics can be controlled. They are myoclonic in origin – quick and shock-like. However, after a few minutes they need to release these (kept) tics. Blepharospasms cannot be controlled and are sustained. Treatment: Botulinum toxin: 17000 per vial; lasts for 3-6 months; 4 sites around the eyes (eg. Inner and lateral canthi, upper and lower eyelids, frontalis: less frowning), corrugators ○ uses 20units, 1/5 the vial ACCORDING TO BODY DISTRIBUTION Focal ○ Single body part is affected (neck ayes hand) ○ Example: writer’s cramp, torticollis (neck dystonia), blepharospasm (frequent eye blinking) Segmental ○ 2 or more contiguous areas affected ○ E.g. Meige’s Syndrome: blepharospasm and opening dystonia of the jaw (eyes and mouth are affected) Multifocal ○ 2 or more non-contiguous areas affected ○ E.g. dystonia in legs and hands Generalized ○ One or both legs, the trunk, and some other parts of the body, or all TASK SPECIFIC DYSTONIA ACCORDING TO ETIOLOGY X LINKED DYSTONIA-PARKINSONISM (XDP) Primary or Idiopathic ○ Oppenheim dystonia (DYT 1) Secondary or Symptomatic ○ Drug-induced (neuroleptics such as haloperidol), perinatal cerebral injury (cerebral palsy patient), trauma, stroke, tumor, encephalitis, Multiple sclerosis, metabolic, psychogenic Dystonia-plus Syndrome (non-neurodegenerative) ○ Dopa-responsive dystonia (DYT 5): Has a problem in metabolism of dopamine (no tyrosine hydrolase) if you give levodopa, the dystonia will disappear Diurnal pattern (better in morning but gets worse towards the end of the day) ○ Myoclonus et dystonia (DYT 11) Heredo-degenerative ○ X-linked dystonia-parkinsonism (DYT 3) ○ Wilson’s disease ○ A Filipino disease Dystonia only found in Filipinos (mostly in Panay) DYT 3 (more specific term), “lubag” (more general term for abnormal movements) ○ DYT3: called such because it was the 3rd dystonia to be described ○ “Lubag”: Ilonggo term for any twisting movement Adult-onset then generalized, predominantly male (99%); X linked recessive; male manifests/female are carriers Severe, progressive movement disorder with high degree of penetrance and a high frequency of generalization Sensory tricks: alleviate the dystonic movements (e.g. putting something on the mouth, dancing, touching the face) Characterized by dystonic movements, usually starting in the 3rd or 4th decade, spreading to generalization within 2-5 years (mean age: 39.4 years old) Mean age of death is 55 Most common cause of death is suicide The dystonia co-exists with or is replaced by parkinsonism usually beyond the 10th year of illness. Diagnostic Criteria of XDP o Presence of a movement disorder manifesting as Dystonia alone or in combination with Parkinsonian traits o Mostly males (5 females as of 2011) CHUA, COPE, CORALDE Seen in frequent repetitive movements Writer’s cramps (with index fingers pointing outwards, extension) Also described in milkers, seamstresses, cobblers, shoemakers, musicians and others with work involving repetitive movements Athlete’s task-specific dystonia When patient is doing something, dystonia comes out. Dual Dystonia: Writer’s cramps + difficulty in buttoning the pants Mirroring: when you ask the right-handed patient to write with his left hand, muscles of the right finger may also extend along with the left (can be observed in most cases) Treatment: isolate the muscle group affected, inject with Botulinum toxin Page 3 / 7 Lec 11: Disorders of Basal Ganglia Sample Case from Sir: 57 y.o. woman with Turner’s syndrome developed dystonia at 50 y.o. o Adult onset o Family history of XDP (must go back 2-3 generations to make pedigree) o Sample family: fourth generation men are >50% affected and the third generation females are carriers o S/Sx shown in the video: lingual tremors, protrusion, jaw opening, lid retraction, truncal extension, hip flexion, lateral flexion, tip toeing o Sensory Tricks e.g. disappearance of dystonia when dancing Origin of XPD cases (proportion may be attributed to health care): ○ Aklan – 17% ○ Capiz – 63% (where the doctors go frequently) ○ Antique – 2% ○ Iloilo – 12% ○ Guimaras – 0.23% Table 2. Total number of XDP cases examined as of 2010=505 Total no of surviving patients= 312 PLACE/PROVINCE Philippines Panay Island Capiz* Aklan Iloilo Antique Guimaras OS 211 DYSTONIC MOVEMENTS o Parkinsonism phase: atrophy of the caudate nucleus, dilatation of frontal horn of the ventricle, BOTH striosomes and matrix are severely depleted PARKINSONISM hypokinetic movements Reduced neuron specific expression of the Taf1 gene is associated with X-linked dystonia-parkinsonism (Makino et al., 2007) o Expression of TAF1 (TATA-binding protein-associated factor 1 gene) and dopamine receptor D2 gene (DRD2) in the caudate nucleus is significantly decreased by a disease-specific SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu composite) retrotransposon insertion in an intron of TAF1 , which encodes the largest component of TFIID complex. o Abnormal pattern in DNA methylation in the retrotransposon in the genome from caudate of the patient is also attributed to the decreased expression of TAF1 gene. o Genogram is useful for determining if the diseased is X-linked or autosomally inherited. C. NEUROIMAGING PREVALENCE (100,000) 0.31 5.74 23.66 7.72 1.43 (2001) 0.86 0.73 DYSTONIA WITH NO PARKINSONISM (DYSTONIC PHASE) T2W, T1W, and infrared (IR) images demonstrate mild caudate atrophy and mild putaminal atrophy with high signal rim on T2W represented by enlarged ventricles Table 3. XDP statistics Age at onset Age at initial examination Duration of illness from onset Duration of illness from onset to generalization* Duration to predominant parkinsonism Duration of survival Age of surviving cases Age at death MEAN 39.67 RANGE 12-64 yrs 44 16 4 20-70 yrs 1-41 yrs 1-23 yrs 14 12.04 51.14 55.59 7-25 yrs 1-41 yrs 28-86 yrs 30-92 yrs *84% generalized in 5 years; most of the patients commit suicide – low duration of survival, bed sore infection aspiration, younger age of surviving cases and age of death. Figure 4. MRI of the brain of a patient with dystonia without parkinsonism. DYSTONIA WITH PARKINSONISM (PARKINSONISM PHASE) Normal curvature of the structures are also lost (like the ventricles), severe caudate atrophy with ex vacuo dilatation of the frontal horns and severe putaminal atrophy with slit-like high-signal intensity of T2W and low signal intensity of T1W Figure 5. MRI of the brain of a patient with dystonia with parkinsonism. Figure 3. Basal Ganglia Circuit of Dystonia and Parkinsonism Phases Phases of XDP (Goto et al., 2005): o Dystonia phase: striosomes atrophy, and are severely depleted, matrix is relatively spared hyperkinetic/dystonic disorders (Dystonia is manifested in patients with XDP due to disproportionate involvement of neostriatal compartments and their efferent projections as postulated by Goto et al. (2005) based on three-pathway model of basal ganglia. There is an imbalance in the activity between the striosomal and matrix-based pathways leading to dystonia.) LOSS OF STRIOSOMES IN THE STRIATUM HENCE CHUA, COPE, CORALDE D. OTHER DYSTONIAS CRANIOFACIAL DYSTONIA Dystonia that affects the muscles of the head, face, and neck o Blepharospasm, stare (lid retraction), mouth opening, neck dystonia, some drool continuously; may have laryngeal involvement (voice also affected); note hypertrophied SCM (very prominent) OROMANDIBULAR DYSTONIA Affects the muscles of the jaw, lips, and tongue. The jaw may be pulled either open or shut, and speech and swallowing can be difficult TRUNCAL DYSTONIA Involuntary activation of muscles of the chest, abdomen, or back. o Involuntary back arching, extension torsion, or lateral bending APPENDICULAR DYSTONIA Page 4 / 7 Lec 11: Disorders of Basal Ganglia Some dystonic tremors, hyperextended extremities/fingers, a lot of them have up-going toes (extension) so some cut off their toes, some may have flexion GAIT DYSTONIA “Bird walk”; hamstrings are tight GENERALIZED DYSTONIA Hip flexion, still able to walk but with poor balance, bended forward, torsional dystonia After 10 years Parkinsonian (sensory tricks no longer applicable) E. TREATMENT No definitive treatment; Zolfidem seems to be the best with optimal effects in an hour but addictive and with decreasing effect with chronic use. GENERALIZED AND SEGMENTAL DYSTONIA Levodopa or carbidopa: up to 300 mg/day to diagnose doparesponsive dystonia Anticholinergics: biperiden, trihexyphenidyl Baclofen: muscle relaxant Benzodiazepines: sedative Dopamine depletors: to decrease peripheral dopamine; tetrabenozine Clonazapam, Clonadine FOCAL DYSTONIA Botulinum toxin A injection precisely applied to the affected muscle group SURGICAL TREATMENT Bilateral chemopallidotomies or bilateral thalamotomies Deep brain stimulation o Costs around 2.5M pesos o 88.3% decrease of the BFM Dystonia Rating Scale, without incurring any persistent adverse effects o Generally safe & effective procedure for alleviating the disabling symptoms of XDP in contrast to previous ablative surgeries performed o Rechargeable battery good for 8-9 years, must be replaced after, costs around $25,000 OS 211 Axial rigidity is more prominent than appendicular rigidity Pseudobulbar dysarthria Frontal dysexecutive syndrome=Memory impairment No available treatment. Initially improved in Levodopa unsustained but MULTIPLE SYSTEM ATROPHY (MSA) Characterized clinically by parkinsonism, dysautonomia, cerebellar dysfunction Hallmark: dysautonomia o Patients have orthostatic hypotension, imppotence. Previously described as: not used anymore o Shy-Drager Syndrome o Striato-nigral Degeneration (SND) o Olivopontocerebellar atrophy (OPCA) MSA-P (if predominant symptom is parkinsonism) or MSA-C (if predominant symptom is cerebellar dysfunction) MSA is synonymous with striatonigral degeneration when parkinsonism predominates (MSA-p), with olivoponto cerebellar atrophy (OPCA) when MSA-c signs predominate, and with Shy-Drager syndrome when autonomic failure is dominant (Shrivastava, 2007). More common in men, usually at the 6th decade; death occurs 7-8 years after the initial symptoms Pathology is in the dorsolateral striatum and ventrolateral portion of the globus pallidus and substantia nigra: glial cytoplasmic inclusions Patients have difficulty standing up or with foot tapping. Severely bradykinetic. Hot cross bun sign on MRI (“never mind not gonna come out.”) The hot cross bun appearance is seen in patients with MSA-c. The sign is due to a selective loss of myelinated transverse pontocerebellar fibers and neurons in the pontine raphe with preservation of the pontine tegmentum and corticospinal tracts. Other investigators have demonstrated a similar pattern of neuronal loss in a patient with parkinsonism, the neuronal loss being secondary to presumed vasculitis, and proposed that the sign may reflect Wallerian degeneration of transverse pontocerebellar fibers secondary to vasculitic infarction. Regardless of the mechanism, this pattern of selective neuronal depletion results in a cross-shaped hyperintensity in the pons on T2-weighted MR images (Shrivastaya, 2007). VII. PARKINSONISM A neurological syndrome manifested by any combination of 6 cardinal features: o Resting tremor o Bradykinesia/hypokinesia/akinesia o Rigidity o Flexed posture of neck, trunk and limbs o Loss of postural reflexes o freezing Characterized by hypokinesias (in contrast to dystonia which is characterized by hyperkinesias) Categories: Primary (Parkinson’s Disease), Parkinsonism-Plus Syndromes (PSP, MSA, CBGD, Lytico-Bodig), Heredo-degenerative Disorders (Hallervorden-Spatz Disease, Neuroacanthocytosis, Wilson Disease) Antipsychotic drugs can cause parkinsonism Figure 6. Transverse T2-weighted MR image of the brain of a patient with multiple system atrophy (MSA) of the cerebellarpredominant subtype (MSA-c) shows the hot cross bun sign as a cruciform hyperintensity in an atrophied pons (arrow). Cerebellum and middle cerebellar peduncle (arrowheads) are also atrophied, with increased signal intensity. (Radiology, 245:606–607) A. PARKINSONISM-PLUS SYNDROMES Parkinsonism occurring with other signs, vertical gaze paresis, hypotension, dysautonomias, and apraxia Exhibits poor response to levodopa (as compared to Parkinson’s Disease which is responsive to levodopa) Endemic among Guamanians PROGRESSIVE SUPRANUCLEAR PALSY (PSP) History of frequent falls due to postural instability is central to the diagnosis of PSP Wrinkled or surprised look Vertical supranuclear gaze paresis (difficulty moving head) could not move the eyes vertically can be overcome via vertical doll’s eye maneuver Memory problem Unsteady gait with erect posture Postural instability Symmetric bradykinesia and hypokinesia Tremor is rare CHUA, COPE, CORALDE CORTICOBASAL GANGLIONIC DEGENERATION (CBDG) Also called corticodentatonigral degeneration with neuronal achromasia and cortical-basal ganglionic degeneration Asymmetrical Parkinsonism Idiomotor Apraxia Presents in the sixth or seventh decade with a slowly progressive, unilaterally jerky, tremulous, akinetic, rigid, and apraxic limb held in a fixed dystonic posture and displaying the alien limb syndrome. However, symptoms and presentations vary. The behavioral manifestations in CBD may also include language disturbances and frontal lobe-type behavior. Barely follows Frontal executive dysfunction LYTICO-BODIG DISEASE Endemic among Guamanians (LBD : Guam : XDP : Philippines) B. HEREDO-DEGENERATIVE DISEASES Page 5 / 7 Lec 11: Disorders of Basal Ganglia WILSON DISEASE Inborn error of copper metabolism (low ceruloplasmin) Hepatic cirrhosis and basal ganglia damage (hepatolenticular degeneration: lentiform nucleus) Autosomal recessive trait; chromosome 13q14.3 Defective incorporation of copper into ceruloplasmin o Low serum ceruloplasmin level Manifestation: Neurological in ~40% adult; hepatic in ~40% pediatric; psychiatric illness in ~15% Wing-beating tremor: large-amplitude tremor when arms are extended and after a short latency arms are thrown up and down; lessened after chelation Kayser-Fleischer rings (EYES): brownish-yellow ring visible around the corneo-scleral junction (limbus); consists of copper deposits in Descemet’s membrane, extending into the trabecular meshwork; can be seen via slit lamp Figure 6. Kayser-Fleischer rings. Symptoms: o Akinetic-rigid syndrome o Generalized dystonia o Postural, intention tremor with ataxia, titubation, dysarthria Treatment: o Chelators D-penicillamine with pyridoxine Trientine Zinc & tetrathiomolybdate Dimercapol (BAL) o Liver transplant – best treatment o Dietary restriction (avoid copper-containing food sources like prunes, cocoa, black pepper, and yeast) OTHERS Hallervorden-Spatz Disease Neuroacanthocytosis C. PRIMARY: PARKINSON’S DISEASE "It's like driving with the emergency brake on." - Patient with PD (You want to speed up but you cannot.) Named after James Parkinson, who provided a detailed description of what he termed "shaking palsy" in an essay published in 1817 A chronic progressive disorder of motor function primarily of middle to late life (no longer true because there are already young patients) Nine genetic linkage loci Can result from (1) decreased dopamine production, (2) insensitive postsynaptic receptors or (3) early (or increased) degradation on synaptic cleft by enzymes o Factors leading to the degeneration of the substantia nigra are uncertain o Genetic susceptibility + environmental toxin In more than 90% of patients, the cause is unknown Gross examination of the brain in PD reveals mild frontal atrophy with depigmentation of the substantia nigra OS 211 Microscopically, there is degeneration of the dopaminergic cells with the presence of Lewy bodies in the remaining neurons and processes of the substantia nigra pars compacta The pathologic changes in the substantia nigra involve dopaminergic neurons that project to the striatum and thus lead to depletion of dopamine in the caudate nucleus and putamen. The depletion of dopamine leads to complex changes in the striatal projection neurons, with similar effects on thalamocortical projections over both the direct and indirect pathway. DIRECT PATHWAY: Decreased nigrostriatal excitation of D1 receptors decreases the striatal inhibition of neurons in the internal segment of the globus pallidus and the substantia nigra reticulata. Consequently, the pallidothalamic and nigrothalamic inhibition of thalamocortical neurons become enhanced. END RESULT: decreased cerebral cortical excitation over thalamocortical projection fibers. INDIRECT PATHWAY: Decreased nigrostriatal inhibition of D2 receptors increases the striatal inhibition of neurons in the external segment of the globus pallidus. This decreases the inhibitory effects of external segment pallidal neurons on subthalamic nucleus neurons and thereby enhances the excitatory effects of subthalamic projections on the internal segment of the globus pallidus and substantia nigra reticulata. Consequently, the pallidothalamic and nigrothalamic inhibition of thalamocortical neurons becomes enhanced. END RESULT: decreased cerebral cortical excitation over thalamocortical projection fibers. Figure 8. Natural history of PD and symptomatic treatment. By the time a patient is diagnosed, up to 80% of his dopaminergic neurons are already gone. DIAGNOSTIC CRITERIA UK PD BRAIN BANK CRITERIA Bradykinesia and at least 1 of the following: o Rigidity o Rest tremor o Postural instability not caused by visual, vestibular or proprioceptive dysfunction Exclude other causes of parkinsonism (neuroleptic drugs: haloperidol or amlodipine, ciprofloxacin) At least 3 of the following supportive (prospective) criteria: o Unilateral onset o Rest tremor present o Progressive disorder o Persistent asymmetry (first side is severely affected) o Excellent response to levodopa (70-100%) o Severe levodopa-induced chorea or dyskinesia o Clinical course of > 10 years o GBA gene o Antipsychotic drugs can cause Parkinsonism SYMPTOMS Figure 7. Substantia Nigra CHUA, COPE, CORALDE Parkinsonian tremor: resting tremor o Distal parts of the extremities and lips while the body portion is at rest o Re-emergent tumor: put arms forward, initially no tremor but appears after a while o Ceases upon active movement of the limbs, reemerges when the limb remains in an antigravity posture o If not resting, it must be an action tremor Rigidity: flexed posture o Manifested in the distal limbs by a ratchet ‘give’ when moving a joint throughout its range of motion (cogwheel rigidity) o Accounts for flexed posture Bradykinesia o Decreased frequency of blinking (dry eyes) o Small, cramped handwriting (micrographia) o Drooling (because of difficulty in swallowing) Page 6 / 7 Lec 11: Disorders of Basal Ganglia Bradyphrenia – delayed verbal response, not demented Difficulty with hand dexterity – shaving, brushing,teeth Loss of spontaneous movement – gesturing Masked facies or hypomimia (face less expressive than usual) Soft speech (hypophonia) with loss of inflection (aprosody: monotonous voice) o Slowness in raising shoulder and arm (may even “freeze” since they are not swinging their arms) o Difficulty arising from a chair and turning in bed Loss of postural reflexes o Occurs later in the disease (falls easily, stooped posture, no arm swing) o Pt has difficulty righting himself after being pulled off-balance o Do the “pull test” (pull the patient if he falls without any resistance or effort to stop the fall, it’s a (+), or (-) righting reflex) Freezing o Affects the gait, begins with start-hesitation (feet takes short, sticking, shuffling steps before patient can begin walking) o Feet eventually become ‘glued to the ground’ in crowded spaces; difficulty passing through small doors o Destination-freezing – stopping before reaching the final destination (e.g. Pt falls down upon reaching the door knob) o Visual and auditory cues may help (ex: patient steps on the lines in the floor to guide them while walking) o Motor fluctuations – occurs during severe parkinsonisms and happens when medications are not taken; there is a sudden off to their movement o o o o o MEDICAL TREATMENT Dopamine precursor: levodopa Decarboxylase inhibitor: carbidopa, benserazide Levodopa must be given with carbidopa so that levodopa will not be converted to dopamine peripherally so it can cross the blood-brain barrier COMT inhibitor: prevents breakdown of dopamine (which is degraded by MAO and COMT); entacapone MAO-B inhibitor: also prevents breakdown of dopamine; selegiline Dopamine releaser: amantadine (antiviral) Dopamine agonist: bromocriptine, pergolide, piribedil, ropinirole, pramipexole, apomorphine (injectable dopamine) Meds lose their effect after continuous use (~20 years) Too much levodopa will lead to motor fluctuations (dyskinesia) OS 211 Motor fluctuations Lesioning Therapies Deep Brain Stimulation One surgery Little follow up required No implantable device Cheaper Adjustable Reversible Bilateral Surgical risks irreversible Cannot be done on both sides of the brain (bilaterally) Surgical risks Follow up Device-related complications Expensive END OF TRANSCRIPTION CHUA: Happy holidays Block A! and Blo have supported Project H2O, thank you so much! Let’s all contribute to help the victims in the Visayas! AFTG! COPE: Merry Christmas Block A. Happy valentine’s day??? Block B! Hahaha. Hello sa researchmates ko, sana matapos na tayo. Hi Jana (Ayan binati na kita. Bayad na ako.) CORALDE: Hello sa crush ko. nilagay to ni Cope. Pero sige hello na din!:)) Excited nako! Bukas na ang TRP guys! Let’s sing with all our hearts! Alam nyo nung sinulat ko yung kanta, wala lang, dahil yun ang interpretation ko sa theme na Med and Beyond. Pero nung nameet ko yung mga taga Palo, Leyte last week tapos nagkwento sila tungkol sa nangyari sa kanila dun nung Yolanda, at kung pano kakailangan ang mga doktor sa communities nila, mas nafeel ko yung kanta natin Sana kayo rin, find a reason to sing the song in a way that you really mean it. Ayun lang. good luck to us!:) Bilang last trans namin to for the year, Merry Christmas and thank you Block A and 2017 for a happy 2013! Dopamine (being a very large molecule) cannot cross the BBB; therefore, we must give a precursor such as levodopa. Levodopa should not be given alone because it will be quickly converted to dopamine before it even crosses the BBB. Decarboxylase inhibitor is given to prevent this. Dopamine is easily metabolized by MAO or COMT. Therefore, it must be given with either a MAO inhibitor or a COMT inhibitor. SURGICAL OPTIONS Thalamotomy of the opposite side (Michael J Fox had this!) Ablative lesions of the pallidum and subthalamic nucleus Deep brain stimulation o Pacemaker-like technology delivers electrical pulses to targeted structures in the brain o Electrical pulses may block brain signals that cause symptoms of PD o Implanted device can be programmed non-invasively to maximize benefit and minimize side effects o Thalamic stimulation for parkinsonioan tremor and essential tumors o With 4 contact points on each side of the brain o Bilateral subthalamic nuclei stimulation for Parkinson’s disease( only in cardinal santos) o It is preferred because it is adjustable, programmable and reversible o Surgery is done with the patient awake to check its positive effects or complications right there and then o Battery must be replaced after 3-5 years o Chemotherapy after surgery but on lower dose to lessen the complication/side effects (dyskinesias and hallucinations) o Criteria Age < 70 5 years with the disease No psychosis or depression Not demented Must be levodopa responsive prior to surgery o Side effects: bleeding, seizures, infection, fractured electrodes Table 4. Advantages and disadvantages of the treatment options. ADVANTAGES DISADVANTAGES Medication side effects Levodopa Ease of use increase over Therapy Adjustable time;hallucinations; CHUA, COPE, CORALDE Page 7 / 7