Neurological Differential Diagnosis

172 Chapter 4 Secondary CDH 1 Post-traumatic headache 2 Cervical spine disorders 3 Headache associated with vascular disorders 3.1 Arteriovenous malformation 3.2 Chronic subdural hematoma 3.3 Vasculitis: including temporal arteritis 3.4 Dissection: usually more acute and associated with neck pain +/– focal neurological signs 4 Intracranial infection: Epstein-Barr virus, HIV, etc. 5 Pseudotumor cerebri 6 Neoplasm 7 Sinusitis 8 Temporomandibular joint (TMJ) disorder 9 Analgesic rebound headache

Neurological Differential Diagnosis: A Prioritized Approach Roongroj Bhidayasiri, Michael F. Waters, Christopher C. Giza, Copyright © 2005 Roongroj Bhidayasiri, Michael F. Waters and Christopher C. Giza Chapter 5 Neuropsychiatry and Dementia Approach to neurobehavioral evaluation 174 Neuropsychiatric interview 174 Clinical correlates of mental status impairment 175 Dementia evaluation 177 Neuropsychiatry and behavioral neurology 178 Clinical signs and symptoms 178 Disorders of perception 178 Memory disturbances 178 Transient global amnesia vs. psychogenic amnesia 179 Visual hallucinations 180 Auditory hallucinations 181 Pharmacologic agents and toxins associated with hallucinations 182 Neurological disorders and associated behavioral disorders 183 Neurological conditions that have depression as a prominent feature 183 Neurological causes of mania 184 Neurological conditions associated with psychosis 185 Neurological causes of episodic dyscontrol or violence 186 Common neurological disorders and associated behavioral disorders 187 Substance abuse and neurological symptoms 188 Neuro-ophthalmologic features of common neuropsychiatric disorders 189 Serotonin syndrome vs. neuroleptic malignant syndrome 190 Regional correlates of neuropsychiatric symptoms 191 Psychotic symptoms associated with focal brain abnormalities 192 Neuropsychological deficits associated with lateralized hemispheric damage 193 Dementia and delirium 193 DDx of dementia 193 Differentiating dementia and delirium 194 Criteria for diagnosis of probable Alzheimer disease 195 Infectious causes of dementia 196 173

174 Chapter 5 Rapidly progressive dementia 197 Creutzfeldt-Jakob disease: sporadic form versus variant 198 DDx of delirium or acute confusional state 199 Hydrocephalus and dementia 201 Specific behavioral syndromes like aphasia, apraxia, etc. are covered in Chapter 2. Approach to neurobehavioral evaluation Neuropsychiatric interview • Assessing the patient’s general appearance is the first observation made in the neuropsychiatric examination. For example: a disheveled appearance reflecting a lack of self-care occurs in frontal lobe syndromes; a unilateral dressing disturbance occurs in hemispatial neglect. • Disturbances of motor function are among the most revealing aspects of the neuropsychiatric examination. For example: 1) retarded depression is characterized by psychomotor slowing, long latencies of reply, and paucity of verbal output; 2) catatonic behavior with stereotypy and waxy flexibility can be seen in affective disorders. Components of the neuropsychiatric interview and mental status examination 1 Interview: ◆ Appearance: well-groomed, disheveled ◆ Motor behavior: restless, akathisia, tremor, waxy flexibility ◆ Mood and affect: depressed, energized, cheerful, flat, blunted ◆ Verbal output: sparse, verbose, pressured ◆ Thought: circumstantial, flight of ideas, perseveration ◆ Perception: misperceptions, illusions, hallucinations 2 Mental status examination: ◆ Attention and concentration: digit span forward and backward ◆ Language: fluency, comprehension, reading, writing, repetition ◆ Memory: registration, immediate and delayed recall ◆ Construction: drawing objects ◆ Calculation skills: mathematics, word problems ◆ Abstraction: similarities, proverbs

Neuropsychiatry and Dementia 175 ◆ Insight and judgment: problem solving, hypothetical examples (what would you do if …?) ◆ Praxis: ability to perform complex motor tasks (brush teeth, comb hair, etc.) ◆ Frontal lobe system tasks: executive planning, Luria hand sequence ◆ Right-left orientation ◆ Finger identification Clinical correlates of mental status impairment • When testing mental status, remember there is a hierarchy of performance. If the patient is unable to perform a basic task, then detailed testing of higher functions will not necessarily reflect a specific localization-related deficit. • Basic tasks include tasks of attention, language, and recognition. If a patient is unable to attend (such as in an acute confusional state/delirium), then deficits in memory or calculations, etc. should be interpreted with caution. Similarly, if a patient demonstrates a receptive aphasia, then failure to complete other tasks may not reflect additional deficits, but merely the inability to follow the examiner’s commands. • It is generally sensible to test basic functions first, and then modify the level of detail of the remainder of the mental status exam based on performance of these basic functions. Test Abnormal performance Clinical correlates of poor < 5 digits performance Attention Digit span Delirium Advanced dementia ‘A’ test: series of letters, Errors of omission Conduction aphasia patient identifies all ‘A’s Delirium Serial subtraction Erroneous subtraction Frontal lobe dysfunction Delirium Dementia Acalculia, amnesia Digit span backwards < 4 digits Delirium Dementia Reversed spelling Slowing or failure Frontal lobe syndrome Delirium Dementia Frontal lobe syndrome Continued

176 Chapter 5 Clinical correlates of poor Test Abnormal performance performance Memory Recall & recognition impaired Amnesia with left hemispheric lesions Word list learning Cortical dementia Word list learning Recall impaired, recognition Frontal subcortical system dysfunction intact Figure learning Figure learning Recall & recognition impaired Amnesia with right hemispheric lesions Remote recall Recall impaired, recognition Frontal subcortical system dysfunction intact Remote recall Variable: temporal gradient Amnesia present Impaired: no temporal gradient Dementia Language Fluent aphasia Posterior left hemispheric lesion Spontaneous speech Non-fluent aphasia Spontaneous speech Impaired Anterior left hemispheric lesion Comprehension Impaired Repetition Impaired Posterior left hemispheric lesion Naming Left perisylvian lesion Writing Agraphia Reading Alexia without agraphia Left or right hemispheric lesion Delirium Alexia with agraphia Dementia Word list generation Reduced Left parietal lobe lesion Left medial occipital lesion (and splenium?) Left parietal lobe lesion Anomia Left frontal lobe lesion Psychomotor retardation Miscellaneous Acalculia Left inferior parietal lesion Calculation Concrete Abstraction Dementia Frontal lobe syndrome Judgment Impaired Dementia Motor programming Perseveration Frontal lobe syndrome Praxis Apraxia Lateral convexity of frontal lobes Left hemispheric lesion Corpus callosum

Neuropsychiatry and Dementia 177 Dementia evaluation • There is no single battery of laboratory tests that would adequately screen for all causes of dementia. In addition, many syndromes lack pathognomonic laboratory features that would allow such identification. • Correct diagnosis of a dementing illness depends critically on the integration of clinical history, neurological, and general physical examinations, and mental status assessment as well as selected laboratory tests. • Laboratory assessment of patients with suspected dementia is targeted to identify REVERSIBLE causes, with a core group of laboratory tests that should be performed on all demented patients for this purpose. Ancillary investigations are recommended when suspicion for a specific diagnosis is high. 1 Core laboratory tests ◆ Complete blood count ◆ Serum electrolytes, calcium, glucose, blood urea nitrogen, creatinine, liver function tests ◆ Thyroid-stimulating hormone ◆ Serum vitamin B12 ◆ Structural imaging study 2 Ancillary investigations ◆ Syphilis serology (RPR) ◆ Sedimentation rate (ESR) ◆ HIV testing ◆ Chest X-ray ◆ Urinalysis with 24-hour urine collection for heavy metals and toxicology screen ◆ Neuropsychological testing ◆ Apo-E genotyping, Aβ42/tau CSF analysis ◆ Electroencephalography ◆ Single-photon emission computed tomography (SPECT) ◆ Positron emission tomography (PET) Note: apolipoprotein E genotyping is not useful in isolation from the clinical cri- teria of Alzheimer disease, but may increase the sensitivity of the diagnosis when patients do not have the Є-4 allele. Another biomarker for diagnosis of Alzheimer disease is the combined assessment of CSF amyloid β(1–42) protein (Aβ42) and tau concentrations, which has a sensitivity of 85% and specificity of 87%.

178 Chapter 5 Neuropsychiatry and behavioral neurology Clinical signs and symptoms Disorders of perception • Abnormalities of perception may be classified according to modality (visual, auditory, touch, olfactory, and gustatory) and whether they represent positive or negative phenomena. • Disorder of visual perception is the most common disorder of perception seen in clinical practice. 1 Positive phenomena ◆ Hallucinations: formed or unformed distortions occurring without external stimulus ◆ Illusions: distortions or misinterpretations of existing stimuli ◆ Palinopsia: visual images that persist even when gaze direction changes 2 Negative phenomena ◆ Unilateral neglect ◆ Blindness ◆ Achromatopsia (central color blindness) ◆ Agnosia (inability to recognize) ◆ Visual object agnosia ◆ Prosopagnosia (agnosia for familiar faces) ◆ Environmental agnosia (agnosia for familiar places) ◆ Simultagnosia (inability to perceive multiple objects as a single entity at once) ◆ Color agnosia Memory disturbances • For clinical purposes, memory disturbances can be divided into those that are short-lived (less than 24–48 hours) and those that are more prolonged. • Alternatively, memory disturbances can be divided into stable and progressive. • Amnesia refers to a specific clinical condition in which there is an impairment in the ability to learn new information despite normal attention, preserved ability to recall remote information, and intact cognitive functions. • Amnesia should be distinguished from other causes of memory disturbances associated with lapses of consciousness including seizures, alcoholic blackouts, migraine, etc.

Neuropsychiatry and Dementia 179 1 Transient episode of memory loss (< 48 hours) 1.1 Amnesia ■ Transient global amnesia (TGA) – (see below) ■ Psychogenic amnesia ■ Post-traumatic amnesia 1.2 Memory lapses associated with alterations of consciousness ■ Seizures ■ Alcoholic blackouts ■ Migraine ■ Toxic-metabolic confusional states ■ Benzodiazepine-induced amnesia 2 Prolonged period of memory loss (> 48 hours) 2.1 Amnestic syndromes ■ Head trauma ■ Wernicke-Korsakoff syndrome ■ Herpes simplex encephalitis ■ Hippocampal infarction ■ Basal forebrain lesions 2.2 Dissociative states ■ Fugues ■ Multiple personality disorders 2.3 Minimal cognitive impairment (MCI) 2.4 Dementias ■ Alzheimer disease ■ Subcortical dementias Transient global amnesia vs. psychogenic amnesia • Psychogenic amnesia is most likely to be confused with transient global amnesia (TGA), especially in patients presenting with acute onset. • However, there are several characteristics that aid in the differentiation of psychogenic amnesia from TGA. • The most important clue is that TGA almost never includes a loss of personal identity, whereas it is one of the hallmarks in psychogenic amnesia. • Psychogenic amnesia should also be distinguished from episodic disturbances of consciousness, such as those associated with complex partial seizures. • The exact cause of TGA is still unclear. However, recent cerebral blood flow studies suggested diminished blood flow in the posterior hemispheric and inferior temporal regions.

180 Chapter 5 Transient global amnesia Psychogenic amnesia A distinct clinical syndrome consisting of an Hysterical conversion symptom in which patients acute period of amnesia lasting less than 24 suddenly forget their identity and life situations hours Personal identity retained Personal identity lost Unable to learn new information Ability to learn new information preserved Amnesia not selective Memory loss may be selective for specific information Temporal gradient present, with relative Temporal gradient absent preservation of remote memory beyond the period of retrograde amnesia Depression and anxiety infrequent Depression and anxiety common Distressed by amnesia Indifferent to amnesia Common in older patients (5th to 7th Common in younger patients (teens–3rd decades) decades) Visual hallucinations • There are no etiology-specific or pathognomonic types of hallucinations, though features of visual hallucinations may facilitate identification of the clinical disorders from which they originate. 1 Lilliputian hallucinations ◆ Vision of tiny humans and animal figures, named after the diminutive inhabit- ants of the Isle of Lilliput. ◆ They are distinctive but appear to have little etiologic significance. They have been described in toxic/metabolic disorders, epilepsy, ocular diseases, affective disturbances, and schizophrenia. 2 Brobdingnagian hallucinations ◆ Hallucinations of giants. ◆ Have been reported in a small number of acute confusional state cases. 3 Autoscopy (heutoscopy) ◆ Striking hallucinations in which one sees one’s own image. ◆ May suggest underlying organic brain disorders including epilepsy, tumor, trauma, subarachnoid hemorrhage, migraine, and infections.Also occurs with schizophrenia and depression. 4 ‘Psychedelic’ hallucinations ◆ Characterized by geometric forms, spirals, funnels, and chessboards that are most characteristic of the hallucinogenic drugs. However, can also occur with

Neuropsychiatry and Dementia 181 sensory deprivation, and have been described in CNS disorders such as during recovery from acute viral encephalitis and with acute occipital lobe insults. 5 Palinopsia ◆ A unique form of visual hallucination that involves the persistence or recurrence of visual images after the exciting stimulus has been removed. The images re- main when the patient changes direction of gaze and may spontaneously recur. ◆ Palinopsia can occur with lesions in either hemisphere, but is most common with acute damage to the posterior aspect of the non-dominant hemisphere. ◆ It has also been reported as a possible side-effect of trazodone and LSD intoxi- cation. Auditory hallucinations • Auditory hallucinations, unlike visual hallucinations, are more characteristic of idiopathic psychiatric disorders than of neurological or toxic metabolic disorders. • An important exception to this observation is the common occurrence of auditory hallucinations in schizophrenia-like psychosis that may be associated with a variety of medical and neurological disorders. • Unformed auditory hallucinations are called tinnitus, whereas formed hallucinations consist of melodies and occasionally voices. • Deafness and auditory hallucinations appear to predispose to the development of paranoia in the elderly. • Musical hallucination is a unique type of auditory hallucination and is most common with deafness. It can also be caused by central nervous processes, such as epilepsy, and can occur with depression and schizophrenia. Etiologies of auditory hallucinations: 1 Psychiatric disorders: the most common cause of auditory hallucinations ◆ Schizophrenia, occurs in 60–90% of patients ◆ Depression ◆ Mania ◆ Post-traumatic stress disorder 2 Toxic metabolic disorders ◆ Chronic alcoholic hallucinosis ◆ Occurring as part of delirium? 3 Peripheral lesions ◆ Deafness can be caused by the disease of middle ear, inner ear, and auditory nerve. This may produce both unformed and formed hallucinations. 4 CNS disorders ◆ Temporal lobe epilepsy ◆ Pontine lesions

182 Chapter 5 Pharmacologic agents and toxins associated with hallucinations • Among all medications, hallucinations commonly occur with four major groups: hallucinogens, anti-Parkinsonian medications, drugs associated with withdrawal syndromes, and a miscellaneous group. • Any medications, when taken in excess, may produce an acute confusional state with concomitant hallucinations. 1 Hallucinogens ◆ Lysergic acid diethylamide (LSD) ◆ MDMA (ecstasy) ◆ Ketamine ◆ Abused inhalants, including ether, gasoline, glue, and nitrous oxide. 2 Antiparkinsonian medications: all anti-Parkinsonian medications have been reported to cause hallucinations. ◆ Anticholinergic drugs ◆ Levodopa ◆ Dopamine agonists, including pramipexole, ropinirole, pergolide, and bro- mocriptine ◆ Amantadine ◆ Selegiline ◆ Catechol-O-methyltransferase inhibitors (COMTI), including entacapone and tolcapone 3 Drugs associated with withdrawal syndromes ◆ Barbiturates ◆ Benzodiazepines ◆ Chloral hydrate ◆ Opiates ◆ Ethyl alcohol 4 Miscellaneous ◆ Cimetidine ◆ Digoxin ◆ Lithium ◆ Antidepressants, e.g. imipramine ◆ Corticosteroids ◆ Propanolol ◆ Disulfiram ◆ Thyroxin ◆ Amphetamines ◆ Sympathomimetics

Neuropsychiatry and Dementia 183 Neurological disorders and associated behavioral disorders • Depression is a broad term that encompasses changes in mood as well as a complex clinical syndrome. It includes sadness, anhedonia, and impaired ability to experience pleasure. • The interaction between depression and neurological diseases is complex. When depression precedes the onset of neurological disease, it is usually unclear whether the depression is the first manifestation or coincidentally preceded the onset of the brain syndrome. • Depression itself can cause cognitive impairment, resulting in a dementia syndrome of depression or pseudodementia. • In general, depression is under-recognized in neurological conditions and even when recognized, patients tend to be under-treated for depression. Neurological conditions that have depression as a prominent feature 1 Multiple sclerosis ◆ Up to 80% of patients with multiple sclerosis have depressive symptoms. ◆ In addition, treatment with interferon ß-1b has been associated with new- onset depression. 2 Extrapyramidal diseases 2.1 Idiopathic Parkinson disease (PD) and other Parkinsonian syndromes ■ Approximately 50% of PD patients will experience depressive episodes during the course of illness. ■ Risk factors include female gender with a past history of depression. ■ Depression in PD is associated with more impaired cognitive function, the presence of psychotic features, and greater disability. ■ Profiles of depression in PD include dysphoria, pessimism, and promi- nent somatic symptoms with less guilt and self-blame. ■ In other Parkinsonian syndromes, depression is observed in: ■ 20% of patients with progressive supranuclear palsy ■ 75% of patients with corticobasal ganglionic degeneration ■ 50% of patients with diffuse Lewy body disease 2.2 Huntington disease (HD) ■ Approximately 40% of patients with HD have mood disorders. ■ The mood change in HD is not just a reaction to the illness, but reflects the underlying neuropsychiatric manifestation of the disease. ■ HD is also associated with a marked increased in suicide rate, up to 8 times greater among patients age 50–69 years old compared to a control group.

184 Chapter 5 3 Primary degenerative dementias ◆ Alzheimer disease (AlzD) and frontotemporal dementia ■ Patients with cortical dementia tend to exhibit less severe depression than those with subcortical disorders. ■ Approximately 40% of AlzD patients have depression. 4 Cerebrovascular disease ◆ Up to 33% of stroke patients will experience depression. ◆ Correlation between stroke location and risk of depression has been contro- versial. ◆ Vascular depression is a rather new term, suggesting that the late-onset de- pression is related to silent cerebral infarction and subcortical white matter lesions. 5 Epilepsy ◆ Depression in epilepsy patients may occur as part of a prodromal emotional change, part of an aura, part of an ictal manifestation, following seizures as part of the post-ictal state and lastly, may be an interictal manifestation. ◆ Interictal depression is the most common type of psychopathology observed in epilepsy patients and is associated with complex partial seizures with left- sided foci. ◆ Situational depression may also occur and can result from anticipation of sei- zures, reduced socialization, and decreased work productivity. ◆ Interactions between anticonvulsants and antidepressants should always be considered in each patient. Monoamine oxidase inhibitors are least likely to exacerbate seizures. 6 Others ◆ Traumatic brain injury ◆ CNS infections ◆ Cerebral neoplasms Neurological causes of mania • Mania is usually primary but may be secondary to other medical conditions. • The most common associations are with lesions in the right hemisphere involving the orbitofrontal cortex, caudate nuclei, thalamus, and basotemporal area. 1 Right hemispheric lesions ◆ In epilepsy, hypomania is usually seen peri-ictally, in the setting of clusters of right-sided temporal seizures. ◆ Other causes have been reported, such as stroke, and traumatic brain injury. 2 Parkinson disease with dopaminergic therapy

Neuropsychiatry and Dementia 185 3 Huntington disease ◆ Depression is more common than mania in HD. 4 Multiple sclerosis 5 Frontal lobe degeneration 6 Tertiary syphilis Neurological conditions associated with psychosis • Psychosis is defined as a loss of reality testing such that affected individuals cannot evaluate the accuracy of their perceptions or thoughts and draw incorrect inferences about external reality. • A wide variety of neurological, toxic, and metabolic disorders cause secondary psychosis as their presenting manifestation, or as one aspect that emerges during the course of illness. • The most common condition associated with psychosis is schizophrenia, followed by dementia of Alzheimer disease. 1 Drug intoxication ◆ Acute psychosis (including paranoia, agitation, and hallucinations) can result from intoxication, particularly with amphetamine, cocaine, phenylcyclidine (PCP), mescaline, LSD, and psilocybin. 2 Primary degenerative dementias ◆ Three common primary degenerative dementias associated with delusions are Alzheimer disease, diffuse Lewy body disease, and frontotemporal dementia. ◆ 40–70% of patients with Alzheimer disease manifest delusions, making it the most common cause of psychosis after schizophrenia. ◆ Delusions in Alzheimer disease are usually simple, loosely held, and often tran- sient. Typically, Alzheimer patients experience delusions of spousal infidelity, monetary theft, or uninvited strangers coming to the house. 3 Extrapyramidal disorders ◆ Psychosis is more frequent in hyperkinetic diseases than in patients with hy- pokinetic disorders. A good example is Huntington disease in which psychosis is one of the major manifestations. Others include Wilson disease, idiopathic basal ganglia calcification, and spinocerebellar degeneration. ◆ In hypokinetic disorders, psychosis is common in postencephalitic Parkinson- ism (von Economo encephalitis) with delusions in up to 25% of cases. Psycho- sis is much less common in idiopathic Parkinson disease and usually occurs in the setting of a medication-induced effect. 4 Central nervous system infections ◆ Herpes simplex encephalitis preferentially involves the medial temporal lobes, inferior frontal areas, and cerebral cortices that are included in the limbic