involves lifestyle and pharmacological therapies to treat fatigue, neurogenic/ spastic blad der, and tremor, as well as gait problems and other physical impairments. Fampridine (4-ami nopyridine) has been shown to improve impaired walking in patients with MS, but with risk f or seizure. Transverse myelitis Transverse myelitis is an inflammatory demyelinating disease restricted to the spinal cord. Patients present with acute to subacute onset of myelopathic symptoms. There are usually prominent motor, sensory, and bowel/bladder symptoms. This disease is us ually monophasic, but some patients experience recurrences. Risk factors for recurrence inc lude underlying autoimmune condi- tions such as Sj gren \200\231s or serology suggestive of an underlying condition (e.g., positive SSA/anti-Ro or SSB/anti-La antibodies). In the appropriate clinical set- ting of a acute/subacute myelopathy, imaging (MRI with gadolinium ) must be obtained to rule out compressive lesions, intrinsic masses, or vascular lesions, and a LP should be obtained to confirm evidence of inflammation (i.e., mild pleo- cytosis o r elevated IgG index). Absence of an enhancing lesion on MRI or pleo- cytosis within the CS F should prompt a search for an alternative diagnosis. Differential diagnosis Longitudinall y extensive transverse myelitis across multiple spinal levels can occur in Sj gren \200 \231s, lupus, sarcoidosis, or neuromy- elitis optica, whereas shorter segments are more typ ical for MS. An MRI of the brain should be obtained to evaluate the patient for possible MS . White matter lesions within the brain in association with a spinal cord demyelinat- ing e vent could indicate that the myelopathy is in fact the first symptom of MS. Other pathologi es that should be considered include neuromyelitis optica (see below), dural AV fistula, sa rcoidosis, spinal cord tumor, spinal cord infarct (venous and arterial), and compressive my elopathies. Treatment of transverse myelitis has two components, specific treatments to red uce the degree of inflammation and supportive care given to all patients with spinal cord p athology. Specifically for the transverse myelitis, high-dose IV steroids (1 g/d methylpred nisolone for 5 d) is the standard of care. For patients not improving on this therapy, plas mapheresis and/or pulse-dose cyclophosphamide is indicated. 376 Neuromyelitis optica (Devic \200\231s) Neuromyelitis optica (Devic \200\231s syndrome) is a demyelinating condition that is primarily restricted to the optic nerves and the spinal co rd. Clinically, it pres- ents as either an optic neuritis (diminished vision in one eye acc ompanied by pain with movement of that eye) or as an episode of transverse myelitis. Some p atients diagnosed as having transverse myelitis will actually go on to have the initial dia gnosis of Devic \200\231s syndrome after they have an episode of optic neuritis. MRI of the entire CNS with gadolinium is warranted to evaluate for evidence of MS. Patients with neur omyelitis optica (NMO) tend to progress more rap- idly than MS patients and do not respond to interferons or glatiramer acetate. A circulating IgG antibody to aquaporin 4 (anti-NMO) has been identified in a large number of NMO patients, suggesting a humoral etiology. Thus, these patients may respond best to plasmapheresis, IV immunoglobulin (IVIG), or immunosupp ressants with humoral activity. Immunomodulatory monoclonal antibody therapies are being te sted for potential disease-modifying effects, but none is yet part of a standard or approve d treatment regimen. Dementia The hallmark of dementia is impaired cognition with intact consciousness (unlike d elirium). Most causes are progressive and irreversible. The key is a good history: Ask spouse, relatives, or friends about progressively impaired cognition/memo ry. Get objective evidence. Histories usually go back months or years. There is worsening f orgetfulness, and normal tasks of daily living are done with increasing incompetence, such as going to the store several times in a day and then being baffled as to why there is a gr eat quantity of food in the kitchen. Sometimes the patient will exhibit personality change such as apathy, uncharacteristic rudeness, or literalness. For objective evi- dence, do tes ts of cognitive functioning. Epidemiology Rare <55 yrs. 5 \200\22310% prevalence >65 yrs. 2 0% prevalence >80 yrs, and 70% in those >100 yrs. y g o o r u e N l Common causes Alzheimer \200\231s disease (AD) ; see below . Vascular dementia: 25% of all dementias. It represents the cumulative effects of many small strokes. Look for evidence o f vascular pathology (hypertension, past strokes, focal CNS signs). Onset is sometimes sudd en, and deterioration is often stepwise (vs. slowly progressive). Lewy body dementia: Chara cterized by Lewy bodies in brainstem and neo- cortex, fluctuating cognitive loss, alertness , and attention; parkinsonism; detailed visual hallucinations; falls; loss of consciousness /syncope. It is the third most common dementia (15 \200\22325%) after AD and vascular cause s. Neuroleptics in these patients often cause neuropsychiatric symptoms. Parkinsonism is po orly responsive to levodopa. Frontotemporal dementia: Frontal and temporal atrophy without Alzheimer histology. Signs: Behavioral/personality change; early preservation of epi- sodic memory and spatial orientation; disinhibition; hyperorality, stereo- typed behavior, and e motional unconcern. Rarer causes: Alcohol/drug abuse, Huntington \200\231s, CJD, Parkinson \200\231s, corti- cobasal ganglionic degeneration, HIV, cryptococcosis, subacute sclerosing panencephalitis (SSPE), progressive leukoencephalopathy. Ameliorable causes Hypothyroidism , vitamin B 12 deficiency, thiamine deficiency (alcoholics),pellagra (B 3 /niacin deficienc y)syphilis, some cere- bral tumors (e.g., parasagittal meningioma), chronic subdural hemato ma, normal-pressure hydrocephalus (dilatation of ventricles without signs of \206\221 ICP, possibly due to obstructed CSF flow from subarachnoid space; CSF shunts help if patients r espond positively to high-volume LP; it is sug- gested by incontinence early-on and gait ap raxia), intracranial hypotension (rarely). Tests Before consigning a patient to the diagnos is of an irreversible demen- tia, make absolutely certain that no treatable cause of progre ssive mental status decline is missed, however unlikely. Assess for underlying or super- im posed delirium. Complete blood count, ESR, electrolytes, LFTs, ammonia level, TSH, B 12 , R PR/FTA, HIV, CT/MRI, and consider EEG. Treat depression if present. Nuclear imaging studies (single proton emission CT [SPECT), positron emission tomography [PET] with amyloid labeli ng) and spinal fluid sampling (A 42, tau, others) may be useful in specific instances to confirm a specific neurodegenerative etiology. 377 Alzheimer \200\231s disease This leading cause of dementia is currently having a huge impac t on our health care system, nursing home system, and society. As our population continues to live longer, a greater portion will suffer from this disease, requiring increasing atten tion from their children and families. Mean survival 7 \200\22310 yrs from onset. Suspect A lzheimer \200\231s in adults with enduring, acquired deficits of visual-spatial skill ( \200\234he gets lost easily \200\235), memory, and cognition; e.g., tested by mental test s cores + other neuropsychometric tests. Cause The pathological hallmarks of AD is accumulation of \222 -amyloid peptide (a degrada tion product of amyloid precursor protein), progressive neuronal dam- age, intraneuronal ne urofibrillary tangles, increasing numbers of senile plaques, and loss of the neurotransmitt er acetylcholine from damage to an ascending forebrain projection (nucleus basalis of Meyne rt; connects with cortex). Risk factors Defective genes on chromosomes 1, 14, 19, 21; the a poE4 variant is linked to earlier age of onset. Family history confers risk. Incidence is a lso linked to diabetes, cardiovascular risk factors (smoking, hyperten- sion), depression, obesity; exercise (physical and mental, including educa- tional level) may be protective. P resentation Gradual and relentless decline in memory capabilities and cognition, behavioral change (e.g., aggression, wandering, disinhibition), delusions, apathy, depression, irrita bility. There is no standard natural his- tory. Toward end stage, often, but by no means in variably, patients become sedentary, taking little interest in anything. Wasting, mutism, i ncontinence seizures may occur. Diagnosis The absolute diagnosis of Alzheimer \200\231s is based on pathology on biopsy or autopsy. Clinically, neurocognitive testing can identify patients with dementia that is consistent with an Alzheimer \200\231s type. Various diseas e biomarkers (spect, specific labels used with pet scans; increased csf ratios of tau or ph ospho-tau to A \222 42 , mri morphometry, particular panels of mental status tests) are be ing developed, but so far none has proven reliable or widely applicable for definite diseas e, let alone presymptomatically. Treatment The standard of care for AD is cholinergic thera py with cho- linesterase inhibitors. These medications do not cure or reverse the effects o f this dementing illness, but rather slow the progression and delay nursing home placement. A new class of drug, the NMDA receptor antagonist (memantine), has also shown efficacy for delaying the cognitive decline seen in ad. Effective disease-modifying treatments have bee n frustratingly slow in coming, with many promising compounds and approaches falling by the wayside. Otherwise, care is supportive. Epilepsy Epilepsy is a recurrent tendency to spontaneous, intermittent, abnormal electrical activity in part of the brain, manifest as episodic seizures . These may take many forms, but for a given patient they tend to be stereotyped. Convulsions are the motor signs of ele ctrical discharges. Many of us would have seizures in abnormal metabolic circumstances (e.g ., severe hypona- tremia, hypoxia [reflex brief anoxic convulsions after syncope]), but som e patients have a low threshold for having seizures and do not require meta- bolic stresses to have a convulsion. Presentation There may (rarely) be a prodrome lasting hours or days pre- ceding the seizure. It is not part of the seizure itself: The patient or others notice a change in mood or behavior. An aura , which is part of the seizure, may precede its othe r manifestations. The aura may be a strange feeling in the gut, or a sensation or an experi ence such as d j vu (disturbing sense of familiarity), or strange smells, or flashing li ghts. It implies a partial seizure (a focal event), often, but not necessarily, caused by t emporal lobe epilepsy. After a partial seizure involving the motor cortex (Jacksonian convu lsion) there may be temporary weakness of the affected limb(s) (Todd \200\231s palsy). Afte r a generalized seizure, patients experience a headache, myalgias, confu- sion, and letharg y, the so-called postictal state. Diagnosis First, since most seizures are not witnessed by medical personnel, confirming that a reported event was in fact a seizure is not a trivial matter. A detailed description from a witness of the event is crucial. Better still, with 378 the proliferation of digital cameras and mobile phones with video capabilities, it is often possible to educate family members about the importance of capturing a spell for later ins pection. Although a diagnosis based on history is never 100% accurate, certain historical f eatures can increase the odds that an event was epileptic versus syncopal. The presence of prolonged tonic \200\223clonic activ- ity, automatisms, or tongue biting is suggestive of a n ictal event. Syncopal events are often preceded by feelings of light-headedness, vision c hanges, and/or diaphoresis. One or two clonic movements after syncope are not abnormal and can be mistaken for an epileptic event. A more complete differential of recurrent movements includes nonepileptic (psychogenic) sei- zures, tetanus, posturing, rigors, neuroleptic ma lignant syndrome, myoclo- nic jerks, tremors, hemiballismus, dyskinesias, dystonias, migrai ne auras, and metabolic derangements. The attack \200\231s onset is the key for determining what type of seizure is occurring \200\224partial or generalized. If the seizure begins wi th focal features, it is a partial seizure, however rapidly it generalizes. Types Partial o nset seizures: Simple partial seizures, complex partial sei- zures, and secondary generaliz ed seizures. These are often lesional in etiol- ogy. Generalized onset seizures: Absence se izures, myoclonic seizures, clonic seizures, tonic seizures, tonic \200\223clonic seizures, and atonic seizures. These are often genetic or developmental disorders, with widespread a bnormal neuronal dysfunction. Causes Often none is found. Physical: Trauma, space-occupying lesions, stroke, hypertension, tuberous sclerosis, systemic lupus erythemato- sus (SLE), p olyarteritis nodosa (PAN), sarcoid, vascular malformations, Alzheimer \200\231s. Metabolic: Alcohol or benzodiazepine withdrawal; hyperg- lycemia or hypoglycemia, hypoxia, uremia, hy pernatremia, hyponatremia, hypercalcemia, liver disease, drugs (e.g., phenothiazines, tricy clics, cocaine). Infections: Encephalitis, syphilis, cysticercosis, HIV. Workup Careful his tory, toxic-metabolic assessment, imaging, and EEG are indicated for a first seizure (Table 10.19). y g o o r u e N l Table 10.19 Evaluation of adult with first-ever suspected seizure 379 Overriding goals: (1) Determine whether the event was in fact a seizure or some other parox ysmal event. (2) Assess for urgent, dangerous, treat- able pathology or toxic/metabolic der angement. (3) Determine risk for subsequent seizures (epilepsy, requiring ongoing anticonvu lsant therapy) versus likelihood of a one-time event. Obtain as much history as possible fr om patient and witnesses. Try to form an opinion as to whether the witness is reliable. Vid eo of the spell, if available, is invaluable. You must attempt to establish a cause. Adult- onset seizures, particularly with focal features, are often \200\234symptomatic \200\235; i.e., secondary to another structural pathology (or cardiac-, metabolic-, or drug-related p roblem). Clues from the history may point to an obvious illness or other toxic/ metabolic c ause for the seizure. If not, then these tests may help: Urine, electrolytes, LFTs, glucose , calcium, phosphorous, coagulation profiles, and serum and urine toxicology screens. Measu re serum levels of medi- cations. If the patient is not alert on presentation, consider scr eening for common antiepileptics in case the patient is a known seizure patient on medicati on and subtherapeutic. Consider LP if CT shows no signs of \206\221 ICP and there are sign s or symp- toms of a CNS infection. (Continued) Table 10.19 (Continued) Imaging: Don \200\231t assume that if one CT scan is normal, there is no struc- tural lesio n. MRI/MRA should be obtained in all patients to assess for small areas of cortical dysgene sis, tumors, vascular malformations, or cavernomas. Significant cortical or juxtacortical a bnormalities increase risk for subsequent seizures. Routine EEG can help establish risk for subsequent seizure \200\224if positive for focal or generalized spikes, a subsequent seizu re much more likely. Emergent EEG only in cases of suspected status epilepticus, including nonconvulsive. You must give advice against driving (laws vary by state as to physician res ponsibility for reporting), occupational hazards, bathing, swimming, and reproductive issue s if the patient is a woman of childbearing age. Document your discussion. The decision to initiate antiepileptic therapy after a first, unprovoked seizure should be individualized t o the patient. Neurologic consultation is indicated. Epilepsy: Management Involve patients in all decisions . Compliance depends on communicatio n and doctor \200\223patient concordance issues. Living with epilepsy creates many prob- le ms (inability to drive, swim, or bathe alone, or operate machinery) and fears (loss of cont rol, risk of sudden death) and medication issues. Therapy Treat initially with one drug (wi th one doctor in charge) only. Increase doses until seizures are controlled, toxic effects are manifest, or maximum drug dosage reached. Beware of drug interactions, including with h ormonal contraceptive therapies. Most specialists would not recommend treatment after one g eneralized seizure with normal EEG and imaging (in all comers, approximately 50% would have a second seizure in the next few years), but would start treatment after two, at which poi nt epilepsy is likely. Discuss options with the patient. If your patient has only one seizu re every 2 yrs, he or she may accept the risk (particularly if there is no need to drive or operate machinery) rather than have to take drugs every day. 380 Commonly used drugs Carbamazepine: Has indications for partial epilepsy. Starting dose is 4 00 mg/d (divided into bid dosing) with a maximum dose of 2,400 mg/d (in divided doses). Sid e effects include rash, nausea, diplopia, dizziness, fluid retention, hyponatremia, blood d yscrasias. Levels tend to fall over time as the drug induces its own metabolism. Many drug interactions. Gabapentin: Not a particularly potent agent, especially in monotherapy. Has i ndications for partial epilepsy as an adjunctive agent. Typical doses begin at 300 mg/d and can be titrated to a maximum dose of 3,600 mg/d (divided into tid dosing). Side effects in clude weight gain, edema, somno- lence, and rarely heart failure. Pregabalin is a more effe ctive drug with a similar side-effect profile. Lamotrigine: Has indications for generalized and partial epilepsy. Usual start- ing dose for adults is 25 mg bid, titrating as recommen ded to a maximum of 400 mg/d (total dose). Slow titration limits use in patients experienci ng frequent seizures who need to be brought under rapid control. Side effects include rash, Stephens \200\223Johnson syndrome, dizziness, headaches, aplastic anemia, and toxic epider mal necrosis, but, in general, it is well tolerated and has relatively few cognitive effects. Caution when used in conjunction with valproate, as t his will reduce the clearance of lamotrigine (slower/lower titration required). More aggres sive/rapid titration is required when given with carbamazepine. Levetiracetam: Has indicati ons for partial epilepsy and myoclonic epilepsy, but is also useful for seizure disorders w ith secondary generalization. Usual dosing begins at 250 mg or 500 mg bid and can be titrat ed to a maxi- mum dose of 1,500 mg bid. Side effects can include irritability and rarely ps ychosis. Oxcarbazepine: Has indications for partial epilepsy. Starting doses are between 30 0 and 600 mg/d with a maximum dose of 2,400 mg/d (divided into bid dosing). Side effects in clude headaches, dizziness, hyponatremia, and ataxia. Phenytoin: Has indications for genera lized or partial epilepsy. Initial main- tenance doses are around 300 mg/d with dosing bein g altered based on presence or absence of side effects, efficacy, and serum levels of the d rug. Side effects include coarsening of facial features, gum hypertrophy, blood dyscrasias, nystagmus, and ataxia. Significant drug interactions. Topiramate: Has indications for gene ralized and partial seizures. Starting doses are between 25 and 50 mg/d with a maximum dose of 400 mg/d (divided into bid dosing). Side effects include cognitive slowing, weight loss , renal stones, glaucoma, metabolic acidosis, and paresthesias (related to the drugs partia l carbonic anhydrase inhibition activity). Teratogenic, with increased risk for cleft lip/p alate . Zonisamide is a similar drug. Valproate: Has indications for generalized and partia l epilepsy. Starting dose is approximately 250 mg tid with a maximum daily dose of 3,000 mg /d (in divided doses). Side effects: Sedation, tremor, weight gain, hair thinning, ankle sw elling, hyperammonemia (causing encephalopathy), and hepatic fail- ure. Do not use in pregn ancy or in patient planning pregnancy. Lacosamide: A newer, very potent drug, available in PO and IV form. Dizziness is common, and cardiac conduction delay can occur. Newer generati on agents are coming online with regularity, some with more specific indications (e.g., ruf inamide for Lennox-Gastaut syndrome). Therapeutic monitoring Epilepsy patients are mostly m onitored clini- cally, with a seizure diary and surveillance for side effects. Routine drug levels are seldom helpful in the well-controlled patient without side effects, and turnaro und time for test results of newer antiepileptic agents is unac- ceptably long for rapid de cision making. In patients with ongoing seizures, a high therapeutic level could occur with refractory epilepsy but might also raise suspicion nonepileptic seizures. Moderate levels might indicate safety to increase dosing. Extremely low levels might indicate lack of compl iance. In patients with obvious side effects, drug levels may not be necessary to decrease dosing. Changing drugs Indications: On inappropriate drug; side-effects unaccept- able; tre atment failure. Method: Begin new drug at its starting dose, overlap- ping with the first ( being mindful of drug interactions) unless the patient is experiencing toxicity, in which c ase rapid discontinuation may be indicated. Titrate the second drug to a mid-therapeutic le vel, then begin a slow wean off the first if desired. Devices and procedures Vagus nerve st imulators are effective for cer- tain types of epilepsy. Newer implantable seizure detectio n and prevention devices are being developed. In appropriate cases, epileptic foci can be s ur- gically resected after careful brain mapping. Many studies have shown that partial temp oral lobectomy can greatly improve quality of life for selected patients with temporal lobe epilepsy. Corpus callosotomies are seldom y g o o r u e N l 381 performed except in extreme cases. Newer implantable devices are being developed that may b e able to detect and even potentially prevent impend- ing seizures. Status epilepticus Management Status epilepticus (SE) has traditionally been defined as con tinuous seizure activity for 20 \200\22330 min or two seizures occurring without interval r eturn to neurological baseline. Although >90% of all seizures will stop within 2 min, some are prolonged. No emergent therapy is needed for a normal, self-limited seizure. Prolonged convulsive seizures, however, are medical emergencies given the risk of death with status e pilepticus. In addition to airway issues and potential brain injury, serious metabolic dera ngements can rapidly result. Once identified, the management of a patient with SE begins wi th assessment of the airway, acquisition of a rapid blood glu- cose determination (to rule out hypo- and hyperglycemia as easily treatable causes of SE), and establishment of IV acce ss. Labs should be sent for a complete blood count, electrolytes including calcium, ABG, LF Ts, toxicol- ogy, renal function, and antiepileptic drug concentrations. While labs are bei ng analyzed, treatment of SE is initiated with the admin- istration of 0.1 mg/kg of lorazep am intravenously at a rate of 2 mg/min. If seizures continue, the patient should be \200 \234loaded \200\235 with an anticonvulsant, typically with phenytoin or fosphenytoin (lower hemodynamic and extrava- sation risks) at a dose of 20 mg/kg or 20 PE/kg, 1 respectively. If seizures continue despite this load, an additional 10 mg/kg of phenytoin or 10 PE/kg of fosphenytoin should be administered. At this stage, the use of anesthe- sia should be consi dered in conjunction with continuous EEG monitoring. Remember that once a patient is paraly zed for intubation the clinical signs of seizures are lost and frequent or continuous EEG m onitoring is needed to guide therapy. Various other agents may be used. Divalproex, various barbiturates, leveti- racetam, and lacosamide are all available in IV formulations. Propof ol as an agent frequently used during intubation can also be helpful at \200\234breaking \200\235 a seizure. 382 Parkinson \200\231s disease and parkinsonism Parkinsonism is a syndrome of tremor , rigidit y, bradykinesia (slowness) , and loss of postural reflexes. Prevalence 1:200 in people >65. Tremor 3 \200\2236 Hz (cycles per sec). It is most marked at rest during wakeful- ness and coarser than cerebellar tremor. It is typically a \200\234pill rolling \200\235 of thumb over fingers. Rigidity Increased resistance to passive stretch of muscles throughout range of movement ( lead-pipe ); tone may be broken-up by tremor ( cog- wheel rigidity ). Unlike in spasticity, rigidity is present equally in flexors and extensors and is not velocity-dep endent. Bradykinesia Slowness of movement initiation with progressive reduc- tion in speed and amplitude of repetitive actions; also monotonous speech. Expressionless face. Short shu ffling steps with flexed trunk as if forever a step behind one \200\231s center of gravity ( festinating gait ). Feet as if frozen to the ground. Decreased blink rate. Micrographia ( small writing). 1 PE = phenytoin equivalents PD is one cause of parkinsonism; due to degeneration of substantia nigra dopaminergic neuro ns. Symptoms usually start between 50 and 70 yrs and progress steadily. A large proportion of patients will end up with some degree of dementia within 10 yrs. A number of single-gene mutations have been implicated, as have environmental chemical exposures, particularly pes ticides and certain solvents. Due to motor involvement, reduced reaction times, and associa ted visu- ospatial impairments, and side effects from medications (including sleep attacks on dopaminergic agonists), patients with PD suffer from significantly impaired driving abil ity even early in the course of the disease. Surrender of driving license may be medically appropriate . Other causes of parkinsonism include medication exposures such as neuroleptic s (e.g., metoclopramide, prochlorperazine, haloperidol) Lewy body dementia (hallmarks inclu ding fluctuating levels of cognition and alert- ness, visual hallucinations, dementia due t o executive dysfunction early in course); rarely postencephalitis; supranuclear palsy (Stee le \200\223Richardson \200\223 Olszewski syndrome, with absent vertical gaze, both upward a nd down- ward, and dementia); multisystem atrophy (MSA) (formerly Shy \200\223Drager syndro me), with prominent orthostatic hypotension; carbon monoxide poisoning; Wilson \200\231s di sease; communicating hydrocephalus; welding (man- ganese); and microvascular ischemic disea se. Management of PD The goal of therapy is to treat symptoms, restoring function while min imizing side effects. The mainstay of this approach utilizes dopamine precursors and dopami ne agonists. Start drugs when PD is seri- ously interfering with life (not too soon, as lev odopa \200\231s effects wear off with time; explain this to patients and let them choose). Use the lowest dose giving symptom relief without troublesome SEs. In general, L-dopa is th e most effective agent for motor symptoms (indeed, it can be nearly miraculous when first s tarted). The active L-dopa is given with a peripheral dopa decarboxylase inhibitor (in the form of a single tab- let of carbidopa/levodopa) to increase efficacy and reduce GI and oth er side effects. With progression of the disease and prolonged use, however, more frequent dosing is required, and there tends to be a simultanous narrowing of the therapeutic window between the patient being in an unacceptable \200\234off \200\235 state (with severe brad ykinesia and tremor) and frankly dyskinetic due to side effects from the drug. As PD progre sses, strategies that augment delivery of levodopa into the nervous system can be utilized to improve therapeutic effects. Catechol-o-methyl transferase (COMT) inhibitors (tol- capon e and entacapone) can be used to reduce the peripheral and central degradation of L-dopa. O ther side effects of levodopa include orthostasis, and absorption is reduced with food. A t herapeutic trial of carbidopa/levodopa is generally warranted even in cases of seemingly at ypical parkinsonism, titrating from 25/100 mg half-tablet tid with food, up to a maximum of 2 tablets tid without food over a couple of weeks. Lack of responsiveness is the hallmark of non-PD parkinsonism. Many neurologists take the approach of utilizing dopamine agonists in younger patients to spare levodopa for later. The dopamine agonists cur- rently used are either ergotamine derivatives (pergolide and bromocriptine) or nonergotamines (pramipexole , ropinirole, rotigotine). Although these have a lower rate of dyskinesias than L-dopa, the y tend to be less effective for severe symptoms. Side effects can include bizarre, compulsi ve behav- ioral disorders (hypersexuality, gambling, shopping), as well as troublesome slee p attacks. Rotigotine is available in a transdermal patch that may avoid fluctuations that plague oral agents. MAO-B inhibitors (selegiline, rasagiline) are often useful, particularl y adjunctively. Anticholinergic agents can be added to PD therapy regimens y g o o r u e N l 383 in an attempt to improve tremor control. Drugs utilized for this include trihexyphenidyl, b enztropine, and biperiden. Amantadine has been shown to be useful in PD by helping early mi ld symptoms and later by controlling some dyskinesias. In patients with symptoms that progr ess to become refractory to medical management, surgical interventions are available. These include implant- able deep brain stimulators (DBS) of the globus pallidus pars interna or subthalamic nucleus, and lesional surgery (thalamotomy, pallidotomy, subthalamotomy). Nonmo tor symptoms of PD may be sufficiently severe to warrant specific treatment, including asso ciated depression, constipation, and drooling (due to reduced swallowing). Postural instabi lity tends not to respond well to medication. Apomorphine injections can serve to \200\234 rescue \200\235 patients who are \200\234frozen \200\235 in an \200\234off \200\235 state . As yet, neuroprotective or disease-modifying strategies have not been defin- itively prov en effective. Tremor Tremors are involuntary movements involving rapid oscillations. They can be classifi ed based on when they appear \200\224i.e., at rest, during assumption of a posture, or with activity. Classically, rest tremors are seen in PD and other parkinsonian states. Postural and action tremors include essential tremor, metabolic disorders (e.g., hyperthyroidism, h ypoglycemia, pheochromocy- toma) and medication-related tremors (e.g., lithium). One of the most com- mon neurologic causes of tremor is essential tremor. Essential tremor (ET) is a kinetic/postural tremor usually seen in the upper extremities, sometimes involving the head , neck, and voice as well. Generally, it is characterized by low-amplitude, high-frequency movement that can be disabling in its most severe forms. Often, patients identify other fam ily members with similar tremors. More than half of patients will report improvement in the tremor after consumption of alcoholic beverages. Primidone and propranolol are the mainsta ys of therapy for patients with ET. Responses are seen in 50 \200\22375% of patients. Other anticonvulsants are sometimes used (gabapentin, topiramate), and thalamic DBS can be very helpful in severe cases. Non-ET tremor can be difficult to treat. Sometimes weighted silver ware or wrist weights can be used to reduce oscillations. Severe intentional tremor from MS may respond to thalamic DBS. 384 Neuromuscular disease Neuromuscular diseases involve pathologies of the nerve roots, plexus es, nerve axons, myelin sheaths, neuromuscular junctions, and muscles. Patients will compla in of weakness, numbness, or both. Cramping may be present. The pattern of dysfunction is t he clinical key to identifying neuromuscular conditions. Electrophysiology studies (nerve c onduction and electromyog- raphy) serve as an extension of the clinical exam \200\224 they do not replace it ! For example, once a peripheral neuropathy is identified, there is no cl inical means to determine whether the pathology is demyelinating or axonal. A variety of di fferent diseases \200\224often autoimmune \200\224cause demyelinating con- ditions and woul d be treated quite differently than axonal pathologies. A nerve conduction study would iden tify if there were reduced conduction velocities (indicative of demyelination) versus low a mplitudes (signifying axonal loss). The pattern of nerve weakness and numbness is crucial for determining where within the peri pheral nervous system pathology exists. A mononeu- ropathy will give symptoms confined to o ne nerve distribution. A systemic condition causing a polyneuropathy classically affects th e longest nerves first, giving predominantly distal symptoms (toes prior to ankles). The fo llowing section reviews neuromuscular disease from a clinical standpoint. y g o o r u e N l Mononeuropathies These are lesions of individual peripheral and cranial nerves. There are a variety of causes, including trauma, diabetes, heavy metal exposure, infec- tions such as leprosy, and vasculitides. If more than one peripheral nerve is affected, the term mononeur itis multiplex is used. Causes include diabetes, vasculitis, infections, amyloidosis, rheum atoid arthritis, paraneoplastic syn- dromes, and a variety of hereditary diseases. Median n erve C6 \200\223T1 At the wrist (e.g., lacerations; carpal tunnel syn- drome \200\224see Ta ble 10.20): Weakness of abductor pollicis brevis and sensory loss over the radial 3 finge rs and palm. Lesions confined to the anterior interosseous nerve: Weakness of flexion of th e distal phalanx of the thumb and index finger. Proximal lesions (e.g., at the elbow) may s how combined defects. Ulnar nerve C7 \200\223T1 Vulnerable to elbow trauma and at the wrist . Signs: Weakness/wasting of medial (ulnar side) wrist flexors; weakness/wasting of the int erossei (cannot cross the fingers) and medial two lumbricals (claw hand); wasting of the hy pothenar eminence, which abolishes finger abduc- tion and sensory loss over the medial 1 fingers and the ulnar side of the hand. Flexion of fourth and fifth DIP joints is weak. Tre atment: See Table 10.21. With lesions at the wrist (digitorum profundus intact), claw hand is more marked. Radial nerve C5 \200\223T1 This nerve opens the fist. Damaged by compressio n against the humerus (commonly seen with humeral fractures). Test for wrist and finger dro p with elbow flexed and arm pronated. Sensory loss: Variable; test dorsal aspect of root of thumb. Sciatic nerve L4 \200\223S2 Damaged by pelvic tumors or fractures to pelvis or femu r. Lesions affect the hamstrings (knee flexors) and all muscles below the knee (foot drop), with loss of sensation below the knee laterally. Common peroneal nerve L4 \200\223S2 Frequ ently damaged as it winds round the fibular head by trauma or tight-fitting casts. Lesions lead to inability to dorsiflex the foot (foot drop), evert the foot, extend the toes \200 \224and sensory loss over dorsum of foot. Tibial nerve S1 \200\2233 Lesions lead to an inab ility to stand on tiptoe (plantar flexion), invert the foot, or flex the toes. Sensory loss over the sole. 385 Table 10.20 Carpal tunnel syndrome: The most common mononeuropathy Nine tendons and the median nerve compete for space within the wrist. Compression is common , especially in women who have narrower wrists but similar-sized tendons to men. The patien t: Aching pain in the hand and arm (especially at night) and paresthesias in the thumb, ind ex, and middle fingers, all relieved by dan- gling the hand over the edge of the bed and sh aking it. Some patients experience referred pain into the forearm and shoulder. There may b e sensory loss and weakness of abductor pollicis brevis with or without wasting of the then ar eminence. Light touch, two-point discrimination, and sweating may be impaired. Associati ons: Pregnancy, rheumatoid arthritis, DM, hypothyroidism, dialy- sis, trauma. Tests: Neurop hysiology helps by confirming the lesion \200\231s site and severity (and likelihood of imp rovement after surgery). Maximal wrist flexion for 1 min (Phalen \200\231s test) may elicit symptoms but is unreliable. Tapping over the nerve at the wrist induces tingling (Tinel \200\231s test; also rather nonspecific). Treatment: Splinting of the wrist for 3 \200\2236 months may help. If not, local steroid injection may be temporizing. Surgical decompressio n (tradi- tional or minimally invasive) is quite effective in the long run, but at the expe nse of slight reduction in grip strength and initial immobility during recovery. Table 10.21 Managing ulnar mononeuropathies from entrapments The ulnar nerve is in an anatomically precarious position and is subject to compression at multiple sites around the elbow. Most commonly, compression occurs at the epicondylar groov e or at the point where the nerve passes between the two heads of the flexor carpi ulnaris mus- cle (true cubital tunnel syndrome ). Trauma can easily damage the nerve against its bo ny confines (the medial condyle of the humerus \200\224the \200\234funny bone \200\235). No rmally, the ulnar nerve suffers stretch and compression forces at the elbow that are modera ted by its ability to glide in its groove. When normal excursion is restricted, irritation ensues. This may cause a vicious cycle of perineural scarring, consequent loss of excursion , and progres- sive symptoms \200\224without there being any antecedent trauma. Rest and av oiding pressure on the nerve helps but if symptoms continue, nighttime soft elbow splinting (to prevent flexion to >60 degrees) is warranted for a few months. For chronic neuropathy associated with weakness, or if splinting fails, a variety of surgical procedures have been tried. For moderately severe neuropathies, decompressions in situ may help initially but s ubsequently fail. Medial epicondylectomies are effective in 50% (there is a high rate of re currence). SC nerve reroutings (trans- positions) may be tried. IM and submuscular transpos itions are more complicated, but the latter may be preferable. Compressive ulnar neuropathi es at the wrist ( Guyon \200\231s canal \200\224between the pisiform and hamate bones) are less common, but they can also result in disability. Thoracic outlet compression is anothe r cause of a weak, numb hand. Electromyography (EMG) helps define the anatomic site of lesi ons. 386