Paget disease


Bone, pain, nerve compression, frontotemporal dementia

Definition and epidemiology

Paget disease of the bone, also known as osteitis deformans, is the most common bone disorder after osteoporosis. It affects about 3% of the population in the United States, has no gender preference, and increases in incidence after age 50.


Abnormal osteoclastic, and later osteoblastic, activity results in sclerotic, trabecular bone remodeling, which weakens the skeleton, most commonly in axial locations. Etiology may be related to stimulation of the immune system via viral antigens, particularly measles, but family history is also present 40% of the time, suggesting a possible genetic predisposition. A genetic mutation in the valosin containing protein (VCP) or RIN3 gene combines Paget disease, frontotemporal dementia and familial inclusion body myositis.

Clinical presentation

Because pain is usually a late complication, many people, perhaps as many as 70%, may be asymptomatic. Primary bone pain is described as dull, deep, and predominantly nocturnal. Pain secondary to complications is more frequent than primary pain, especially due to the neurological entrapment or joint deformities. Bone pain typically increases with rest and weight bearing, as well as with limb warming and at night. The neurologic complications are usually the result of osseous overgrowth causing nerve compression, resulting in deafness, radiculopathy, and spinal stenosis, as well as cranial neuropathy and brainstem compression. Neurological symptoms may also be related to a vascular steal syndrome. These are overshadowed, however, by the potential for malignant transformation to osteosarcoma and high-output cardiac heart failure due to hypervascularization of the bone marrow.


X-ray findings are specific, showing early lytic or late sclerotic changes, but are not very sensitive. Bone scans can increase sensitivity but are less specific. Biochemical markers, including bone-specific alkaline phosphatase and urinary pyridinoline, have replaced urinary hydroxyproline as a more accurate marker of disease activity and severity.


Bisphosphonates or, less commonly, calcitonin is typically started on symptomatic patients, asymptomatic patients with involvement of weight-bearing regions, or when serum alkaline phosphatase levels rise above 125% of normal. Pain usually responds to nonsteroidal anti-inflammatory medications. Suspicion of osteosarcoma requires oncology consultation.



Pain, nociceptive pain, neuropathic pain

Pain is the most common reason Americans seek medical care. The International Association for the Study of Pain has defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of tissue damage, or both.” The pain experienced by a patient is dependent upon not only any physical source of pain, but also on the patient’s physiological and psychological milieu.

There are neural mechanisms that modify the transmission of pain and the emotional reaction to it.

Pain can be nociceptive or neuropathic. The sensation of nociceptive pain is produced physiologically, generated by the stimulation of peripheral nociceptors or afferent nerve fibers in response to a noxious stimulus. An example would be the pain felt in a tissue injury. Neuropathic pain arises from a lesion or dysfunction of neural structures, such as the burning one feels in diabetic polyneuropathy.

Physiologic pain sensations are carried by multiple anatomical pathways. The spinothalamic tract is a major pain pathway: cutaneous afferent nociceptive fibers enter the dorsal horn of the spinal cord, where they may ascend or descend one to two segments as Lissauer tract. Primary afferents terminate in the superficial layers of the dorsal horn in an area known as the substantia gelatinosa. Second-order neurons decussate and ascend rostrally as the lateral and anterior spinothalamic tracts. The spinothalamic tract projects to the ventral posterolateral nucleus of the thalamus, which then sends its projections to other diencephalic structures, the brainstem reticular activating system, the limbic system, and the primary somatosensory cortex. In addition to the ascending pain system, there is a descending modulation system with origins in the brainstem periaqueductal gray and projections to the raphe nucleus. Projections from the raphe nucleus project directly to the ventral and dorsal horns of the spinal cord, including the substantia gelatinosa, and act to inhibit nociception. Serotonin is the main transmitter in this system. The locus ceruleus also acts as a descending modulating system, using norepinephrine as its transmitter. Prominent within the pain-modulating systems are the opiate receptor system and endogenous opioid peptides, which exist throughout the nervous system, particularly in the periaqueductal gray and raphe nucleus.

Acute pain follows an injury and generally resolves with healing. It has a well-defined temporal onset and is often associated with objective physical signs of autonomic activity such as tachycardia, hypertension, and diaphoresis.

Chronic pain persists beyond expected healing time and often cannot be related to a specific injury. It may not have a well-defined onset, may not respond to treatments aimed at the presumed origin or cause, and may not be associated with signs of autonomic activity; the patients do not “look” like they are in pain.

Complex regional pain syndrome (CRPS) and phantom limb pain are unique chronic pain syndromes. CRPS is characterized by burning pain, hyperesthesia, swelling, hyperhidrosis, and trophic skin and bone changes. It is treated with sympathetic denervation and aggressive physical therapy. (For more information, refer to the chapter on “Complex Regional Pain Syndrome.”) Phantom limb pain differs from the usual nonpainful sensory illusion that the lost limb is still present. Phantom limb pain is refractory to most treatments. Many treatments have been suggested, including mirror therapy and local anesthetic injections, but to date there is insufficient evidence to support any treatment as first line.

Chronic (noncancer) pain requires an integrated multidisciplinary approach directed at both physical and psychological rehabilitation. The goal is to control the factors that increase pain. All therapies, especially drugs, should be given on a time-contingent basis, not as necessary (prn). The patient thus is not rewarded for having pain by getting medication. This approach serves to reduce the total amount of drug required daily. Each drug must be given an adequate trial. Start with simple analgesics, increase the dose or frequency before changing drugs, and when changing, use equianalgesic doses. Avoid excessive sedation.

Pharmacologic management of pain utilizes treatment directed at specific sites along the pain pathways. Peripherally, aspirin and nonsteroidal anti-inflammatory agents produce analgesia by preventing the formation of prostaglandin from arachidonic acid metabolism (inhibition of cyclooxygenase). Prostaglandin sensitizes tissues to the pain-producing effects of bradykinin and other substances resulting from tissue injury. These medications are effective in treatment of mild to moderate pain, especially bone pain. These substances also potentiate the effects of narcotic analgesics. Capsaicin, a derivative of hot peppers, acts by depleting nociceptors of substance P, rendering the skin insensitive to pain. A treatment trial requires 2 to 4 weeks of daily topical application, three to four times per day, to the affected area.

Tricyclic antidepressants (TCAs) act via influencing the biogenic amine system, affecting levels of serotonin, norepinephrine, and dopamine. Patients with pain are often locked into a pain-depression-insomnia cycle, and TCAs can affect each of these aspects of pain. The TCAs are effective in a variety of chronic pain conditions, including chronic low back pain, headache, neuropathy, and neuralgias. Anticonvulsants act to suppress spontaneous neuronal firing. They are useful in the management of chronic pain states such as trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy, and postamputation pain. Venlafaxine, which increases levels of both serotonin and norepinephrine, is emerging as a relatively nonsedating but effective medication for treating neuropathic pain.

Narcotic analgesics are used to treat severe, acute pain and chronic pain. When using narcotics, start with the lowest dose needed to obtain analgesia and titrate to pain relief or to the appearance of unacceptable side effects. Whereas prn dosing for several days allows for the determination of total daily dose, thereafter narcotic analgesics are given on a fixed dosing schedule. Add non-narcotic drugs to increase analgesia. Tolerance to narcotics usually becomes evident as a reduction in duration of analgesia and the need for higher doses. Treat this situation by increasing the dose or by using an alternative drug (start with one half of the equianalgesic dose). The narcotic conversion nomograms can guide conversion between narcotics (Figs. 45 and 46). For example, 30 mg of oral methadone is equivalent to approximately 20 mg of parenteral morphine. Physical dependence occurs if the patient receives prolonged therapy in high doses, and patients experience withdrawal symptoms with abrupt narcotic cessation. Physical dependence is not to be confused with psychological dependence, which is a behavioral syndrome of drug craving.

Fig. 45
Figure 45 Narcotic conversion nomogram: high-potency narcotics. (From Grossman, S. A., & Sheidler, V. R. (1987). An aid to prescribing narcotics for relief of cancer pain. World Health Forum, 8(4), 525–529.)

Fig. 46
Figure 46 Narcotic conversion nomogram: low-potency narcotics. (From Grossman, S. A., & Sheidler, V. R. (1987). An aid to prescribing narcotics for relief of cancer pain. World Health Forum, 8(4), 525–529.)

Other pharmacologic interventions include the use of corticosteroids in the treatment of cancer, especially when cancer is due to bony metastasis; neuroleptics, venlafaxine, or gabapentin in dysesthetic pain; and dextroamphetamine for potentiating narcotic analgesia and reducing narcotic-induced sedation. Antihistamines (hydroxyzine) and neuroleptics can also be used to decrease nausea associated with narcotic use.

Other treatment modalities used in pain management include trigger-point injections; epidural, intrathecal, and sympathetic blockade; ganglionolysis; cordotomy; transcutaneous and percutaneous electrical stimulation; dorsal column stimulation; and relaxation techniques, including biofeedback and hypnosis.


Richardson C., Kulkarni J. A review of the management of phantom limb pain: challenges and solutions. J Pain Res. 2017;10:1861–1870.

Vanderah T., Gould D. Nolte’s the human brain: an introduction to its functional anatomy. ed 7 Philadelphia: Elsevier; 2016.

Paraneoplastic neurologic syndromes


Paraneoplastic neurologic syndromes, cancers, autoimmune, antibodies, immunotherapy

Paraneoplastic neurologic syndromes (PNS) are autoimmune, remote effects of cancer that are not caused by metastatic complications of a systemic cancer. Autoantibodies have been identified in several types of PNS and are summarized in Table 103. Less than 60% of PNS are associated with anti-neuronal antibodies, and neurologic symptoms precede the identification of cancer in only 50% of cases.

Table 103

Antineuronal Antibody-Associated Paraneoplastic Syndromes
Antibody Associated Cancer Syndrome
Anti-Hu (ANNA-1) SCLC, neuroblastoma Encephalomyelitis, sensory neuronopathy
Anti-Yo (PCA-1) Gynecologic, breast Cerebellar degeneration
Anti-Ri (ANNA-2) Breast, gynecologic, SCLC Cerebellar ataxia, opsoclonus
Anti-amphiphysin Breast Stiff-person, encephalomyelitis
Anti-Ma Multiple Cerebellar, brainstem dysfunction
Anti-Ta Testicular Limbic encephalitis, brainstem dysfunction
Anti-Tr Hodgkin lymphoma Cerebellar degeneration
Anti-CAR SCLC, others Photoreceptor degeneration
Anti-CV2/CRMP5 SCLC, others Encephalomyelitis, cerebellar degeneration
Anti-NMDAR Ovarian teratoma Anti-NMDAR encephalitis
Anti-GAD Neuroendocrine, thymoma, small cell lung carcinoma Limbic encephalitis, cerebellar ataxia, stiff-person syndrome
Anti-AMPAR Lung, breast, thymus Limbic encephalitis
Anti-LGI1 Usually none Faciobrachial dystonic seizures, myoclonus, encephalitis
Anti-Caspr2 Thymoma Neuromyotonia, encephalitis, or Morvan syndrome
Anti-mGluR5 Hodgkin lymphoma Ophelia syndrome
Anti-α-GlyR Hodgkin lymphoma Stiff-person syndrome, progressive encephalomyelitis with rigidity and myoclonus
Anti-AchR Thymoma Myasthenia gravis
Anti-GABA-A Hodgkin lymphoma Refractory status epilepticus or epilepsia partialis continua

AchR, acetylcholine receptor; ANNA-1, antineuronal nuclear antibody type 1; ANNA-2, antineuronal nuclear antibody type 2; Caspr2, contactin-associated protein-like 2; CRMP-5, collapsin response mediator protein-5; DNER, delta/notch-like epidermal growth factor-related receptor; GABA, gamma aminobutyric acid A; GAD, glutamic acid decarboxylase; GlyR, glycine receptor; LEMS, Lambert-Eaton myasthenic syndrome; LGI1, leucine-rich glioma-inactivated 1; mGluR5, metabotropic glutamate receptor 5; NMDAR, anti-N-methyl-D-aspartate receptor; PCA-1, Purkinje cell antibody-1; PCA-2, Purkinje cell antibody-2; SCLC, small cell lung cancer; VGCC, voltage-gated calcium channels.

Clinical features that suggest PNS include (1) subacute onset; (2) severe neurologic disability; (3) inflammatory cerebrospinal fluid (CSF) with increased cells, elevated protein, and oligoclonal bands; (4) clinical syndrome that predominantly affects one specific portion of the nervous system; and (5) stereotypical presentation.

There are two main groups: (1) “classic” PNS, in which antibodies when detected almost always indicate that the disorder is paraneoplastic, T-cell mediated with no direct pathologic role of the antibodies targeting intracellular epitopes that are also expressed by the cancer (Lambert-Eaton myasthenic syndrome [LEMS], subacute cerebellar degeneration [SACD], opsoclonus/myoclonus in children), and (2) PNS that can be associated with cancer or appear in the absence of a neoplasm with cell dysfunction directly mediated by antibodies directed at cell surface/synapse epitopes (limbic encephalitis, polymyositis, polyneuropathy). The presence of autoantibodies helps confirm the clinical diagnosis and focuses the search for an underlying malignancy. The mainstays of PNS treatment are immunotherapy and direct tumor therapy. PNS associated with antibodies, directed at intracellular antigens (onconeuronal antibodies), generally respond poorly to treatment; early treatment offers the best chance of recovery. On the contrary, PNS associated with antibodies targeting surface antigens are usually highly responsive to treatments.

PNS includes the following:

  1. I. Brain and cranial nerves: SACD, opsoclonus-myoclonus, limbic encephalitis and other autoimmune encephalitis, paraneoplastic cerebellar degeneration, optic neuritis, photoreceptor degeneration;
  2. II. Spinal cord and dorsal root ganglia: myelitis, necrotizing myelopathy, sensory neuronopathy, subacute motor neuronopathy, motor neuron disease;
  3. III. Peripheral nerves: subacute or chronic sensorimotor peripheral neuropathy, acute inflammatory demyelinating neuropathy, mononeuritis multiplex and vasculitic neuropathy, brachial neuritis, autonomic neuropathy, peripheral neuropathy with islet-cell tumors or paraproteinemias;
  4. IV. Neuromuscular junction and muscle: LEMS, myasthenia gravis, dermatomyositis or polymyositis, acute necrotizing myopathy, carcinoid myopathy, myotonia, cachectic myopathy, neuromyopathy;
  5. V. Multiple levels of central and peripheral nervous system or unknown site: encephalomyelitis, neuromyopathy, stiff-person syndrome.


Cui D., Xu L., Li W.Y., Qian W.D. Anti-Yo positive and late-onset paraneoplastic cerebellar degeneration associated with ovarian carcinoma: a case report. Medicine (Baltimore). 2017;96(32):e7362.

Lancaster E. Paraneoplastic disorders. Continuum (Minneap Minn). 2015;21(2):453–475.

Parietal lobe


Parietal Lobe, Balint Syndrome, Gerstmann syndrome, Somatosensory cortex, Wernicke area

The parietal lobe is located posterior to the central sulcus, superior to the sylvian fissure, and anterior to the parieto-occipital sulcus on the medial surface. The parietal lobe functions primarily in sensory integration of visual, auditory, and somatosensory inputs.

It contains two major sulci: the postcentral sulcus, which marks the posterior boundary of the somatosensory cortex, and the intraparietal sulcus. Extending from the postcentral sulcus dorsally, the intraparietal sulcus separates the parietal cortex into superior (Brodmann area 5 and 7) and inferior parietal lobules, the latter of which contains the supramarginal (Brodmann area 40), and angular gyri (Brodmann area 39) as well as Wernicke area (Brodmann area 22) in the dominant hemisphere.

The postcentral gyrus serves as the primary somatosensory cortex receiving input from the ventral posterior thalamic nucleus and projects to the somatosensory association cortex located in superior parietal lobule (Brodmann area 5).

Clinical presentation of parietal lobe lesions

Unilateral parietal lesion can cause:

  •  Corticosensory syndromes such as astereognosis and agraphesthesia, sensory extinction, neglect (more commonly seen with right parietal lobe lesions)
  •  Homonymous hemianopia or inferior quadrantanopia

Dominant (usually left) parietal lesion may also cause:

  •  Alexia, apraxia
  •  Gerstmann syndrome: dysgraphia, dyscalculia, finger agnosia, right-left confusion

Bilateral parietal lesions cause Balint syndrome, which is characterized by simultanagnosia (inability to perceive more than one object at a time), optic apraxia (difficulty with directing gaze), and optic ataxia.

Parkinson disease


Parkinson disease, degeneration of dopaminergic neurons, substantia nigra, neuronal Lewy Bodies, Tremor at rest, pill-rolling tremor, Rigidity, cogwheel Rigidity, lead pipe Rigidity, Akinesia, Bradykinesia, Levodopa, Dopamine agonists, Carbidopa


Parkinson disease (PD) very rarely occurs before age 30. Symptoms are usually gradual and progressive and include motor and nonmotor symptoms. The nonmotor symptoms include cognitive changes, behavioral/neuropsychiatric changes, and symptoms related to autonomic nervous system dysfunction.

The cardinal symptoms of PD can be remembered using the mnemonic TRAP:

  •  Tremor at rest (4 to 6 Hz, typically pill-rolling of the hands)
  •  Rigidity (cogwheel or lead pipe)
  •  Akinesia/Bradykinesia (slowness, difficulty initiating or fatiguing of movement)
  •  Postural instability (stooped posture/shuffling gait accompanied by poor or absent arm swing)

Symptoms are often asymmetric, and may begin unilaterally, eventually progressing to bilateral involvement. Resting tremor is the presenting symptom in over 70% of patients. Later in the disease course, patients will likely display postural instability.

Other motor symptoms include micrographia (small tapering writing), diminished facial expression (masked facies), hypophonia, stooped posture, shuffling gait accompanied by poor or absent arm swing, and diminished blink rate.

A prodrome of non-motor features may precede motor symptoms of PD by many years. These include: constipation, hyposmia (altered sense of smell), REM-sleep behavior disorder, restless leg syndrome, periodic limb movements of sleep, autonomic dysfunction (e.g., orthostasis and hyperhidrosis, erectile dysfunction), neurobehavioral disorders (depression, anxiety), and urinary urge incontinence.

Differential diagnosis is challenging, given the fact that the classic PD symptoms may be present in other neurodegenerative disorders. Careful history-taking and astute physical assessment coupled with initial medical therapy are necessary to distinguish idiopathic PD from essential tremor, dementia with Lewy bodies, corticobasal degeneration, multiple system atrophy, progressive supranuclear palsy, or secondary parkinsonism (see Parkinsonism chapter).

Neurological imaging may help distinguish PD from vascular parkinsonism, essential tremor, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) but there are no pathognomonic radiographic findings to identify idiopathic PD itself.

Diagnostic criteria have been adopted by the Movement Disorders Society to determine if a patient has “clinically established PD” or “clinically probable PD.” A required feature for either diagnosis is the presence of parkinsonism, defined as bradykinesia plus either tremor or rigidity.

Absolute exclusion criteria include: Unequivocal cerebellar abnormalities; downward vertical gaze palsy; diagnosis of probable frontotemporal dementia or primary progressive aphasia within the first 5 years of disease; parkinsonian features restricted to the lower limbs for more than 3 years; history of medication use consistent with drug-induced parkinsonism; absence of observable response to high-dose levodopa despite at least moderate severity of disease; cortical sensory loss; normal functional neuroimaging of the presynaptic dopaminergic system; presence of an alternative condition likely to produce the patient’s symptoms. If any of these are present, neither “clinically established PD” nor “clinically probable PD” can be diagnosed.

The criteria have also established a set of 10 “red flags” which suggest that the patient may not have PD but are not absolute exclusions. These include: wheelchair dependence within 5 years of onset; complete absence of progression of motor findings over 5 years (unless this can be attributed to treatment); early bulbar dysfunction; inspiratory respiratory dysfunction; severe autonomic failure in the first 5 years; recurrent falls because of impaired balance within 3 years of onset; disproportionate anterocollis or contractures within the first 10 years; absence of any common non-motor features of disease despite 5 years’ disease duration; unexplained pyramidal tract signs; bilateral symmetric parkinsonism. If there are more than 2 red flags, neither “clinically established PD” nor “clinically probable PD” can be diagnosed.

Criteria that support the diagnosis include: Clear and dramatic beneficial response to dopaminergic therapy; presence of levodopa-induced dyskinesia; rest tremor of a limb; the presence of either olfactory loss or cardiac sympathetic denervation on metaiodobenzylguanidine (MIBG) scintigraphy.

If the patient has parkinsonism, has no absolute exclusion criteria, has no red flags, and has at least 2 supportive criteria, then the diagnosis of clinically established PD can be made.

If the patient has parkinsonism, has no absolute exclusion criteria, has 2 or fewer red flags, and the number of red flags is equal to or less than the number of supportive criteria, then the diagnosis of clinically probable PD can be made.


The pathological definition of PD is loss or degeneration of the dopaminergic (dopamine-producing) neurons in the substantia nigra and development of Lewy bodies (a pathologic hallmark) in dopaminergic neurons. Accordingly, dopamine replenishment therapy dominates the therapeutic strategies available for PD patients.


There is no cure for PD, and there is no treatment that can slow or reverse its progress. The central objective for the use of medications in PD is management of the symptoms, both motor and non-motor. All anti-PD medications ameliorate symptoms, rather than change the course of the disease. Thus, dosage and intervals should be titrated to the individual patient’s symptomatic need. The following categories of medications are used to treat PD motor symptoms:

  •  Levodopa
  •  Dopamine agonists
  •  MAO-B inhibitors
  •  COMT-inhibitors
  •  Amantadine
  •  Anticholinergics

These medications, dosages, treatment regiments, indications, and side effects are discussed in detail in Table 104. Clinical management of PD is individually tailored to a patient’s needs with the goal of minimizing “off-time” and extending “on-time.” “Off-time” refers to periods of the day when the medication is not working well, causing worsening of symptoms, whereas “on-time” refers to periods of adequate control of PD symptoms. The following are guidelines helpful in management:

  •  Initial Management

    1. a. If no functional impairment exists, consider disease monitoring and delaying onset of pharmacological management.
    2. b. Carbidopa/levodopa is used effectively as initial monotherapy for management of PD. Concomitant intake of large amino acid loads (protein load particularly in dairy products) will competitively inhibit the transport of levodopa into the brain. COMT-inhibitors extend the benefit of levodopa by reducing “off” symptoms between doses and reducing therapeutic dose beneficial for preventing the nausea that can be caused by levodopa alone.
    3. c. Dopamine agonists are used effectively as a monotherapy in early PD or in combination with carbidopa/levodopa for persistent symptoms. Use is complicated by side effects including compulsive, aggression, and hallucinations. Unadvised for use in the elderly.
    4. d. Anticholinergics agents are used in young people with tremor-predominant PD, though side effects may limit their usefulness. Unadvised for use in the elderly.
    5. e. MAO-B inhibitors used effectively for modest symptom control in early PD or in combination with other medications to reduce “off-time” and extend “on-time”. Drug interactions of medication weaning limit effect utility.

  •  Regiment Modification

    1. a. Gradual decline in responsiveness to levodopa is inevitable. The appearance of motor fluctuations (“wearing-off”) and involuntary movements (dyskinesia) prompts regiment modification.
    2. b. Declining responsiveness to medication initially managed by fractionating levodopa therapy by amount and timing of doses.
    3. c. Increasing motor fluctuations managed by decreasing levodopa therapy and substituting a controlled/slow release carbidopa/levodopa or additional MAO-I.
    4. d. Diphasic dyskinesias managed with increasing the dose of levodopa or switching to a dopamine agonist with a lower dose of levodopa.
    5. e. Amantadine is beneficial in PD patients with prominent tremor or bothersome levodopa-induced dyskinesia.
    6. f. Surgical interventions such as deep brain stimulation (DBS) can be an effective treatment for appropriate patients. These treatments are used in addition to medication.

  •  Non-Motor Symptom Management

    1. a. Depression in PD is best treated with a combination of psychotherapy, antidepressants, and therapeutic physical and mental exercise.
    2. b. Botulinum toxin A can be an effective treatment for severe drooling, although oral and transdermal medications should be tried first in the interest of cost saving.
    3. c. Urinary complaints in PD are typically not responsive to dopaminergic medications but can be remedied by drugs that relax the bladder and allow it to fill to a greater capacity.

Table 104

Medications for the Treatment of Parkinson Disease
Medication Dosages in Milligrams (mg) Typical Treatment Regimens Potential Side Effects Indications for Usage
Carbidopa/levodopa immediate-release (Sinemet) 10/100, 25/100, 25/250 150–1000 mg of levodopa total daily dose (divided 3–4 times) Low blood pressure, nausea, confusion, dyskinesia Monotherapy or combination therapy for slowness, stiffness, and tremor
Carbidopa/levodopa oral disintegrating (Parcopa) 10/100, 25/100, 25/250 150–1000 mg of levodopa total daily dose (divided 3–4 times) Same as above Same as above, plus need for dissolvable medication in mouth especially if swallowing is impaired
Carbidopa/levodopa extended-release (Sinemet CR) 25/100, 50/200 150–1000 mg of levodopa in divided doses, depending on daily need Same as above Monotherapy or combination therapy for slowness, stiffness, and tremor
Carbidopa/levodopa/entacapone (Stalevo) [see COMT-inhibitors below] 12.5/50/200, 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200 150–1000 mg of levodopa total daily dose, depending on daily need Same as above, plus diarrhea and discolored urine (due to entacapone) Replacement for carbidopa/levodopa, for motor fluctuations (benefit of entacapone)
Carbidopa/levodopa extended- release capsules (Rytary) 23.75/95, 36.25/145, 48.75/195, 61.25/245 285–2450 mg of levodopa total daily dose Same as above Monotherapy or adjunct therapy for slowness, stiffness, and tremor.
Note that dosages of Rytary are not interchangeable with other carbidopa/levodopa products.
Carbidopa/levodopa enteral solution (duopa) Clinician- determined Up to 2000 mg of levodopa over 16 hours Same as above For the treatment of motor fluctuations in patients with advanced Parkinson disease
Ropinirole (Requip) 0.25, 0.5, 1, 2, 3, 4, 5 9–24 mg total daily dose (divided 3–4 times) Low blood pressure, nausea, leg swelling and discoloration, confusion, sleep attacks, compulsive behaviors, somnolence Monotherapy or combination therapy for slowness, stiffness, and tremor. Effective in decreasing the required dose of L-dopa and delaying the adverse motor fluctuations
Ropinirole XL (Requip XL) 2, 4, 6, 8, 12, 8–24 mg once/day Same as above Same as above
Pramipexole (Mirapex) 0.125, 0.25, 0.5, 0.75, 1, 1.5 1.5–4.5 mg total daily dose (divided 3–4 times) Same as above Same as above
Pramipexole eR (Mirapex eR) 0.375, 0.75, 1.5, 2.25, 3, 3.75, 4.5 1.5–4.5 mg once/day Same as above Same as above
Rotigotine (Neupro) 1, 2, 3, 4, 6, 8 patch 4–8 mg once/day Same as above Same as above; patch delivery an advantage for some
Apomorphine (apokyn) 30 mg/3 mL vial 2–6 mg Significant nausea; must take anti-nausea medication with dose, especially when starting therapy Adjunct therapy for sudden wearing off; the only injectable, fast-acting dopaminergic drug
Bromocriptine (Parlodel) Cognitive deficit and hallucination tendencies may be exacerbated, and adverse gastrointestinal symptoms and hypotension are not uncommon. Heart valve abnormalities in minority of patients The Food and Drug Administration determined that the risk outweighed the benefit, and removed it from the U.S. market for use in PD in March 200
Pergolide (Permax) Same as above Same as above
Selegiline (l-deprenyl, eldepryl) 5 5 mg once or twice a day Nausea, dry mouth, light-headedness, constipation; may worsen dyskinesia; possible rare interaction with antidepressants and other drug classes Monotherapy for slowness, stiffness, and tremor; adjunct therapy for motor fluctuations. Delay and decrease the need for L-dopa
Rasagiline (azilect) 0.5, 1.0 1 mg once/day Same as above Same as above
Zydis selegiline HCL Oral disintegrating (Zelapar) 1.25, 2.5 1.25–2.5 mg once/day Same as above Same as above, plus need for dissolvable medication in mouth (absorbed in mouth)
Entacapone (Comtan) 200 200 mg 4–8 times daily (with each levodopa dose) Diarrhea, discolored urine, plus enhancing side effects of levodopa, especially dyskinesia confusion, liver failure Combination therapy with levodopa for motor fluctuations. Recommended in advanced PD patients who require greater than 600 mg of L-dopa daily
Tolcapone (Tasmar) 100, 200 100 mg up to 3 times daily Same as above plus increased risk of liver inflammation Same as above (second-line due to side effects)
Amantadine (Symmetrel) 100 mg capsules; 50 mg/5 mL syrup 100 mg 2–3 times daily Nausea, confusion, leg discoloration (livedo reticularis), mild anti-cholinergic effects (see below) Monotherapy for slowness, stiffness, and tremor; combination therapy with levodopa for levodopa-induced motor fluctuations; especially helpful for suppressing dyskinesia
Trihexyphenidyl (formerly artane) 2, 5 mg tablets; 2 mg/5 mL elixir 1–2 mg 2 or 3 times daily—lowering doses (to bid, last dose before 3 PM) is recommended in the elderly Confusion, memory issues, hallucinations, dry mouth, blurry vision, urinary retention, livedo reticularis Monotherapy or combination therapy, predominantly for tremor in younger people; should be avoided in elderly. Utilized mainly for refractory tremor and sialorrhea
Benztropine (Cogentin) 0.5, 1, 2 0.5–2 mg once daily, or divided over 2 doses Same as above Same as above

Table 104Table 104

PD, Parkinson disease.

Surgical options

Surgical therapies are usually reserved for PD patients who are experiencing decreased effects of medical dopamine therapy over time.

  •  DBS is the most frequently performed surgical therapy for PD. In DBS, an electrode is surgically implanted in the subthalamic nucleus, globus pallidus, or ventral intermediate nucleus of the thalamus, providing continuous high-frequency electrical stimulation. Generally, DBS response is best for patients who have had good preoperative response to levodopa and report shorter disease duration (< 16 years). If effective, DBS can help reduce tremor, stiffness, bradykinesia, and effective medication dose.
  •  Surgical lesions for PD include posteroventral pallidotomy (attenuation of bradykinesia, akinesia, rigidity, tremor and long-term improvement of dyskinesia and fluctuations), ventroinferomedial thalamotomy (attenuation of resting tremor, dyskinesia, dystonia, and rigidity) and subthalamic nucleus (attenuation akinetic symptoms).



Parkinsonism, Parkinson disease, Progressive Supranuclear Palsy, Multiple system atrophy, Corticobasal Ganglionic Degeneration, Drug-induced Parkinsonism, Vascular parkinsonism, Secondary parkinsonism, Hallervorden-Spatz disease, Huntington disease, Lubag disease, Wilson disease, Sporadic Pallidal Degeneration, Bilateral Striatopallidodentate Calcinosis, Neuroacanthocytosis, mitochondrial cytopathies with striatal necrosis

Parkinsonism is a general term that refers to a group of neurological disorders that cause movement problems similar to those of Parkinson disease (PD), but distinguished by a known precipitant, atypical presentation, or additional neurologic symptoms. Parkinsonism-plus syndromes may also be seen in a group of heterogeneous degenerative neurological disorders, which differ from classical idiopathic PD in some associated clinical features, poor response to levodopa, distinctive pathological characteristics, and poor prognosis. Parkinsonism-plus syndromes are often misdiagnosed, given subtle clinical differences that require autopsy confirmation.

Progressive supranuclear palsy (PSP)

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative cause of parkinsonism after PD. PSP is classically recognized as a combination of downgaze palsy, progressive rigidity, and imbalance that leads to falls. The distinguishing feature of PSP is the complaint of early onset, postural instability, and frequent falls within the first year that are uncharacteristic of PD. On examination, vertical, slow saccades may be the earliest sign. Ophthalmoplegia is vertical in the majority of patients and upward gaze is affected more than downward, although downward gaze is much more specific because upward gaze restriction is more common in the elderly. Over time, symptoms worsen to include supranuclear ophthalmoplegia, pseudobulbar palsy, axial rigidity, dysphagia, dysarthria, mild dementia, and parkinsonism.

MRI is the modality of choice for imaging patients with suspected PSP. MRI demonstrates atrophy of the dorsal mesencephalon and a widening of the aqueduct, with a decrease in the midbrain-to-pons area ratio, reduction of anteroposterior midline midbrain diameter (e.g., Mickey Mouse sign), lateral margin of the tegmentum of midbrain (e.g., morning glory sign), and a flattening or concave of the midbrain (e.g., hummingbird sign).

There is no specific drug therapy. In the early stages, mild to moderate improvement in symptoms may occur with levodopa or dopamine agonists, but without sustainability. Median survival time is about 5 to 6 years.

Multiple system atrophy

Multiple system atrophy (MSA) is an adult-onset, fatal neurodegenerative disease characterized by progressive autonomic failure, parkinsonian features, and cerebellar and pyramidal features in various combinations. Given variability of clinical presentation, MSA was initially divided between three patterns: Shy-Drager syndrome (autonomic symptoms predominant), striatonigral degeneration (parkinsonian features predominant), and olivopontocerebellar atrophy (cerebellar dysfunction predominant). However, since 2007, MSA has been divided clinically into two MSA-C (cerebellar predominant) and MSA-P (parkinsonism predominant) subtypes.

Like PD, MSA has a prodromal premotor phase, including sexual dysfunction, urinary urge incontinence or retention, orthostatic hypotension, inspiratory stridor, and a rapid-eye-movement sleep behavior disorder that appear months to years before the first motor symptoms. However, unlike PD, as motor features begin to emerge, patients develop disabling dysautonomia, postural hypotension, erectile disturbances, bladder and bowel dysfunction, and hypohidrosis. Patients with the MSA-C generally present with late-onset cerebellar ataxia, while MSA-P may be indistinguishable from PD early in the disease progression. Definitive diagnosis is confirmed only with pathology.

MRI is the modality of choice for imaging patients with suspected MSA. MSA-C subtype typically shows disproportionate atrophy of the cerebellum and brainstem, and MRI T2 hyperintensities typically present in the pontocerebellar tracts (e.g., hot cross bun sign). MSA-P subtype will typically show reduced volume in the putamen with an abnormally high T2 linear rim surrounding the putamen (e.g., putaminal rim sign).

The management of patients with MSA is usually complex. Parkinsonism may respond markedly to levodopa in the early stages, but the response is usually incomplete and short-lived. Patients with MSA have a median survival of 6 years.

Corticobasal ganglionic degeneration

Corticobasal ganglionic degeneration (CBGD) is a neurodegenerative disease that is clinically, genetically, and pathologically similar to frontotemporal dementia. It is defined by asymmetric cortical atrophy, most predominantly in the superior parietal lobule and frontoparietal. Other features include atrophy of corpus callosum, substantia nigra, and bilateral basal ganglia. CBGD is distinguishable from PD by the presence of asymmetrical cortical symptoms and signs.

Onset typically occurs in the sixth decade or later with asymmetrical focal reflex myoclonus and its highly characteristic stiff, dystonic, jerky movements. Patients often present with parkinsonism signs, such as asymmetry dystonia, apraxia, alien limb, and ideomotor apraxia. Other symptoms may include gradual development of aphasia, loss of cortical sensory functions, depression, obsessive-compulsive neurosis, and late onset dementia. Clinically and pathologically, CBGD can present with anterior cortical predominance, manifesting as frontotemporal dementia, or lateral dominant frontal lobe, manifesting as primary progressive aphasia.

MRI is the modality of choice for assessing CBGD. CGBD progresses slowly over the course of 6 to 8 years, and it is often resistant to symptomatic therapy. Death is generally caused by pneumonia or other complications.

Diffuse lewy body disease

Diffuse Lewy body (DLB) is a particular dementia syndrome with features of parkinsonism. Cognitive deficits may emerge in the course of PD; however, DLB is defined by cognitive impairment with later emergence of parkinsonism. Keys to diagnosis include cognitive fluctuation, visual hallucination, and marked neuroleptic sensitivity.

Management of DLB is difficult. If motor symptoms are prominent, these are best managed with small doses of L-dopa; anticholinergic and neuroleptic drugs should be avoided.

Drug-induced parkinsonism

Drug-induced parkinsonism (DIP) is the second most common cause of parkinsonism in the elderly after PD. Many patients with DIP are misdiagnosed with PD because the clinical features of these two conditions are indistinguishable. Moreover, neurological deficits in patients with DIP may be severe enough to affect daily activities and persist for long periods after cessation of the offending agent. In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics (e.g., metoclopramide), calcium channel blockers (e.g., cinnarizine and flunarizine), atypical antipsychotics, MAO inhibitors (reserpine and tetrabenazine), and antiepileptic drugs. Other agents that rarely induce parkinsonism include selective serotonin reuptake inhibitors (SSRIs), lithium, valproate, antiarrhythmics, and diazepam.

Vascular parkinsonism

Vascular or “multi-infarct” parkinsonism is a form of parkinsonism that presents following small strokes. Accounting for less than 5% of parkinsonism cases, patients with vascular parkinsonism often present with sudden onset, asymmetric parkinsonism. This predominantly includes lower body involvement, postural instability, falls, dementia, corticospinal findings, incontinence, or emotional lability.

Secondary parkinsonism

Secondary parkinsonism refers to disorders that are secondarily associated with an akinetic rigid syndrome, which includes postencephalitis, hydrocephalus, hypoxia, trauma, metabolic imbalance (parathyroid), and toxins (manganese, carbon monoxide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], and cyanide). Other diseases with parkinsonism include Hallervorden-Spatz disease, Huntington disease, Lubag disease, Wilson disease, sporadic pallidal degeneration, bilateral striatopallidodentate calcinosis, neuroacanthocytosis, and mitochondrial cytopathies with striatal necrosis. Treatment is symptomatic and consists of elimination of the primary cause.

Aug 12, 2020 | Posted by in NEUROLOGY | Comments Off on P
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