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Cerebral Hemisphere Syndromes 

Cerebral Hemisphere Syndromes

Chapter:
Cerebral Hemisphere Syndromes
Author(s):

Robert B. Darnell

and Jerome B. Posner

DOI:
10.1093/med/9780199772735.003.004
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Paraneoplastic syndromes can affect any portion of the brain, including the cerebral hemispheres (considered here), the brainstem, and the cerebellum (see Chapter 5). Gray matter, white matter, and vasculature may all be affected. Table 4–1 lists some of the syndromes affecting the cerebral hemispheres. Any one of the syndromes listed in Table 4–1 can occur in either an isolated form, affecting only a single area or single cell type in the nervous system, or as part of a more widespread disorder called by Henson and colleagues encephalomyelitis with carcinoma.1 However, even when the clinical findings are restricted to dysfunction of the brain, autopsy studies usually reveal more widespread abnormalities, particularly inflammation.1 The classification given in Table 4–1 is by no means clinically discrete. For example, sleep disorders may occur with either hypothalamic or brainstem dysfunction, or both. Parkinsonian-like syndromes may arise from the basal ganglia or the substantia nigra of the midbrain. Nevertheless, this classification allows a structure for thinking about paraneoplastic neurologic symptoms. With the exception of limbic encephalitis, these disorders are quite rare.

Table 4–1 Paraneoplastic Syndromes Affecting the Cerebral Hemispheres

Site

Clinical Findings

Cortex

Epilepsia partialis continua

Cerebral white matter

Demyelination

Blood vessels (vasculitis)

Infarction

Posterior encephalopathy

Hippocampus (limbic system)

Memory loss (recent memory)

Complex partial seizures

Psychosis

Basal ganglia and thalamus

Dementia

Parkinsonism

Chorea

Hypothalamus

Sleep disorders, cataplexy

Hyper- or hypothermia

Unknown

Cognitive and behavioral abnormalities

CEREBRAL CORTEX (NEOCORTEX)

Paraneoplastic cerebral cortical lesions may be either focal or multifocal. The usual symptom is epilepsia partialis continua (continuous focal seizures that can involve any part of the body, for example, the tongue.2–8 Other patients present with focal cortical signs such as aphasia or hemiparesis with or without seizures.8 In general, isolated focal cortical lesions are a very rare paraneoplastic symptom; most occur in conjunction with limbic encephalopathy 2 or other more widespread brain abnormalities (patient 4–1). A few patients have suffered focal neurologic signs, including hemiparesis,3 aphasia,9 and dysarthria,2 as well as continuous focal seizures (could Oppenheim's original description discussed on p. 8 have been one such disorder?). The electroencephalogram (EEG) often shows continuous or intermittent focal seizure discharges correlating with the clinical symptomatology (Fig. 4–1).

Figure 4–1. EEGs of patient PATIENT 4–14–1 with paraneoplastic encephalomyelitis and focal cortical seizures. A. EEG before the onset of clinical seizures. There is slowing in the left hemisphere consistent with an MRI abnormality there (Fig. 4–2). B. Two weeks later she developed continuous focal seizures. There is right temporal lobe sharp and slow activity that correlates with her seizure activity. Left frontal sharp waves are also seen. The seizures were partially responsive to anticonvulsants.

Figure 4–1.
EEGs of patient 4–1 with paraneoplastic encephalomyelitis and focal cortical seizures. A. EEG before the onset of clinical seizures. There is slowing in the left hemisphere consistent with an MRI abnormality there (Fig. 4–2). B. Two weeks later she developed continuous focal seizures. There is right temporal lobe sharp and slow activity that correlates with her seizure activity. Left frontal sharp waves are also seen. The seizures were partially responsive to anticonvulsants.

PATIENT 4–1

A 72-year-old woman with known chronic lymphocytic leukemia that had been in remission since 2003 and a Clark's level II melanoma that had been removed from her back in 2007, over several days in 2008 almost simultaneously developed difficulty with memory and language, ataxia, and a resting tremor with bradykinesia. Neurologic evaluation revealed findings compatible with Parkinson syndrome as well as memory loss without other cognitive difficulties and cerebellar ataxia. Magnetic resonance imaging (MRI) showed multiple areas of hyperintensity on the FLAIR image involving the medial temporal lobes bilaterally (Fig. 4–2A), the putamen and caudate bilaterally (Fig. 4–2B), and the left cerebellum (Fig. 4–2C). The lesion in the cerebellum was enhancing, but the others were not. Lumbar punctures revealed six to eight white cells with a protein concentration over 100 mg/dL. Cytologic examination showed an increased number of lymphocytes but no clearly abnormal cells. Serum for paraneoplastic antibodies was negative. A stereotactic needle biopsy of the right temporal lobe showed chronic non-necrotizing encephalitis with perivascular and interstitial lymphoid infiltrates and focal mural infiltration of blood vessels by lymphocytes, consistent with paraneoplastic limbic encephalitis. Even in the absence of a paraneoplastic antibody, a paraneoplastic syndrome was considered the likely diagnosis, and the patient was treated with plasma exchange and intravenous immune globulin (IVIg), without improvement in symptoms. Because of the unusual appearance of the cerebellar lesion (Fig. 4–2C), not typical for a paraneoplastic MRI, consideration was given to nervous system lymphoma. However, a biopsy of a cerebellar lesion revealed only lymphohistiocytic infiltrates and necrosis, but without evidence of lymphoma. During hospitalization the patient developed complex partial seizures. An EEG showed spiking of the right temporal lobe (Fig. 4–1). The seizures responded to anticonvulsants. The patient had a stormy course with multiple infections, gastrointestinal bleeding, and the development of a coagulopathy. She died after massive bleeding into the retroperitoneal cavity.

At autopsy, there was no evidence of cancer. The brain appeared grossly normal, save for the biopsy sites. There were multiple lacunar infarcts, particularly in the basal ganglia. Chronic encephalitis, characterized by patchy lymphocytic cuffing blood vessels and interstitial lymphocytic infiltrates, was found in the temporal lobes with patchy involvement of the extratemporal cerebral hemispheres, cerebellum, and midbrain basal ganglia. A vasculitic component was found in the amygdala/hippocampus. The spinal cord and dorsal root ganglia were negative. Immunohistochemical examination revealed a mixed population of inflammatory cells with CD68-positive histiocytes and microglia predominating. Findings were thought to be compatible with a paraneoplastic syndrome.

Figure 4–2. A. FLAIR image demonstrating hyperintensity in the medial temporal lobes bilaterally, as well as cortical and subcortical lesions (arrows). B. FLAIR image demonstrating hyperintensity in the basal ganglia bilaterally and in the right insula (arrow). The basal ganglia lesions or infarcts are a result of paraneoplastic cerebral vasculitis. C. T1 image demonstrating enhancement in the left cerebellum (arrow). Biopsy revealed only inflammation, not tumor.

Figure 4–2.
A. FLAIR image demonstrating hyperintensity in the medial temporal lobes bilaterally, as well as cortical and subcortical lesions (arrows). B. FLAIR image demonstrating hyperintensity in the basal ganglia bilaterally and in the right insula (arrow). The basal ganglia lesions or infarcts are a result of paraneoplastic cerebral vasculitis. C. T1 image demonstrating enhancement in the left cerebellum (arrow). Biopsy revealed only inflammation, not tumor.

Comment

As the electroencephalogram and the seizures illustrate, this patient suffered neocortical involvement, but not in isolation. The MRI identified abnormalities in the basal ganglia that explain the clinical findings of Parkinson's syndrome that were part of her presentation. Paraneoplastic basal ganglia lesions are discussed below. A paraneoplastic vasculitis, also discussed below, was probably responsible for the basal ganglia lesion. An additional point to be made is that even in the absence of a paraneoplastic antibody, the changes were so characteristic as to mandate immunosuppressive treatment. Whether this syndrome was related to the chronic lymphocytic leukemia (we have seen several patients with this disorder who had paraneoplastic syndromes without an identifiable antibody) or the melanoma or was a coincidental (i.e., nonparaneoplastic) illness is unclear.

Both convulsive and nonconvulsive seizures are relatively common in patients with paraneoplastic syndromes affecting the cerebral cortex.10 Convulsive seizures are easily identified and treated with appropriate antiepileptic drugs. Nonconvulsive seizures, particularly nonconvulsive status epilepticus, may be difficult to diagnose, although in some patients, subtle clinical signs such as mild repetitive movements of eye, face, or limb muscles help with the diagnosis. In patients with paraneoplastic syndromes who suffer decreased levels of consciousness, particularly those with anti-NMDA receptor encephalopathy (see Chapter 13), identification of nonconvulsive status epilepticus that may cause or exacerbate the decreased level of consciousness may lead to effective treatment. This is generally done by continuous EEG monitoring, often with video recording of the patient. When nonconvulsive status epilepticus is identified, anticonvulsants are indicated. However, it is often unclear which abnormal EEG patterns are unequivocally epileptic.11, 12 When the diagnosis is unclear, a trial of a benzodiazepine may normalize the EEG and improve the patient's state of consciousness. Unfortunately, in our experience, both the EEG and a trial of benzodiazepine are all too frequently equivocal.

Magnetic resonance imaging may be normal or may demonstrate either focal or multifocal hyperintense FLAIR abnormalities involving the brain gray matter.4, 6, 8 In one instance, resection of a focal area revealed chronic inflammatory infiltrates involving the leptomeninges and perivascular spaces of cerebral cortex and white matter.7 In another instance, a stereotactic biopsy of a right post-central lesion revealed a cortical encephalitis with perivascular infiltrates of B-cells, T-cells, and parenchymal infiltrates of T-cells. There was intracytoplasmic IgG reactivity in some neurons and neuronal cell loss.3 An unusual case of anti-Yo-positive paraneoplastic cerebellar degeneration (PCD) (see Chapter 5) affected a man with adenocarcinoma of the lung. In addition to the cerebellar signs, he had receptive as well as expressive language abnormalities. He died, and at autopsy was found to have cortical abnormalities in the perisylvian area, an area that expressed the Yo antigen.9

Neurologic symptoms usually develop before the tumor has been diagnosed. The most common tumor to cause focal cortical lesions is small-cell lung cancer (SCLC); almost all of the patients tested are anti-Hu antibody positive. In one tumor described as undifferentiated, the Hu antigen was found.5 Rarely, other cancers may cause the same clinical syndrome.1, 13 We have encountered one such patient (patient 4–2).

PATIENT 4–2

A 60-year-old man with a 4-year history of malignant thymoma successfully treated with radiation and chemotherapy was in remission when he awoke from a nap and suffered what was apparently a generalized convulsion. He was admitted to a hospital where he was noted to have 1- to 2-minute episodes of aphasia and a staggering gait. An EEG was negative. An MRI showedmultiple cortical and subcortical hyperintensities on the T2-weighted image, some of which contrast enhanced (Fig. 4–3A). Magnetic resonance spectroscopy (MRS) demonstrated an increased lactate peak (Fig. 4–3B). A brain biopsy revealed only gliosis. Evaluation of serum for paraneoplastic antibodies was positive for CRMP 5 (see Chapter 12) as well as for acetylcholine receptor muscle antibodies. After treatment with anticonvulsants, he remained neurologically well. The MRI, however, waxed and waned, with old lesions disappearing and new lesions appearing. Plasma exchange was unsuccessful because of technical difficulties, but symptoms appeared to respond to corticosteroids. At last examination, the MRI had returned to normal (Fig. 4–3C), except for the biopsy site, and he was neurologically well.

Figure 4–3. A. MRI from patient PATIENT 4–24–2. Multiple areas of primarily cortical hyperintensity can be seen on the FLAIR image. These areas waxed and waned over time. B. Magnetic resonance spectroscopy revealed a high lactate peak, suggesting an inflammatory lesion. The patient responded to corticosteroids (C).

Figure 4–3.
A. MRI from patient 4–2. Multiple areas of primarily cortical hyperintensity can be seen on the FLAIR image. These areas waxed and waned over time. B. Magnetic resonance spectroscopy revealed a high lactate peak, suggesting an inflammatory lesion. The patient responded to corticosteroids (C).

Comment

This patient is remarkably similar to a patient presented by Rickman et al.14 Their patient responded to treatment with plasma exchange. A more recent report identified three patients, two with breast cancer and one with lung cancer, with what the authors called “reversible extra-limbic paraneoplastic encephalopathy.” The major import of the study was a good response to immunotherapy. However, two of the patients suffered a relapsing course.15 Also clinically similar to patient 4–2 is a case report describing a young man with thymoma and CRMP-5 antibodies who developed a relapsing encephalopathy.16 Biopsy suggested vasculitis. The patient made a virtually complete recovery, although new lesions continued to appear on MRI, as it has in our patient. In an article by Ances et al.,13 a similar patient was eventually discovered to harbor anti-AMPAR antibodies (Dr. Josep Dalmau, personal communication).

Most of the pathologic reports have described inflammatory infiltrates, neuronal damage, and IgG within cell bodies—either glial cells, neurons, or both.3, 5

The differential diagnosis includes Rasmussen's encephalitis, also believed to be an autoimmune disorder17 but not associated with cancer. Infections and vascular lesions can also cause epilepsia partialis continua; paraneoplastic antibodies are not found. Geschwind and colleagues18 have described cases of voltage-gated potassium channel encephalopathy (LGI1 [leucine-rich glioma-inactivated] or CASPR2 [contractin-associated protein-like] antibodies; see Chapter 13) that mimic Creutzfeld-Jakob disease. In addition to the rapidly progressive dementia with short-term memory loss (limbic encephalopathy; see later discussion), some patients had myoclonus, extrapyramidal dysfunction, and muscle spasms. In some patients, abnormalities of diffusion-weighted imaging occurred in cortical areas, sometimes associated with focal slow waves and focal epileptic activity.

Treatment is difficult but depends on the specific paraneoplastic problem. For example, although anti-Hu-associated cortical dysfunction rarely responds to treatment, lesions attributed to voltage-gated potassium channels are antibodies (LGI1) often respond to immunosuppression,18 although our experience has not been so salutary (see Chapter 13).8 In most of the reported cases, anticonvulsants were not effective. In one instance, treatment of the tumor caused resolution of symptoms, only to have symptoms recur later as a more widespread encephalomyelitis.4 As indicated above, focal resection of the epileptic focus controlled seizures in one patient7; one patient with thymoma responded to plasma exchange. Our patient responded to treatment with corticosteroids.

WHITE MATTER DEMYELINATION

Paraneoplastic focal19, 20 or multifocal21 demyelinating lesions are rare. They may occur either as an isolated brain lesion20, 21 or as part of a more widespread encephalomyelitis.22 The most convincing cases are those associated with seminoma.19, 20, 22 Jaster and colleagues19 described a 41-year-old man who presented with a right homonymous hemianopsia and was found to have a lesion involving the corpus callosum and surrounding white matter (Fig. 4–4). Biopsy revealed demyelination with preserved axons and perivascular lymphocytic cuffing. No paraneoplastic antibody was discovered. Two months later, a seminoma was discovered. The patient recovered from both illnesses. This patient was also described by Kepes in his report of patients with what is now called tumefactive multiple sclerosis.23 Kepes’ other 30 patients did not have identifiable cancer. Wong and colleagues20 described a 54-year-old man who presented with short-term memory loss and weight loss. An abdominal mass was found on biopsy to be a metastatic seminoma. At the same time, an MRI showed a nonenhancing lesion in the left parieto-occipital lobe that on biopsy was demyelinating. Despite treatment of the tumor, his brain symptoms did not respond, and he was lost to follow-up. One of us (JBP) has seen a similar case. A patient presented by Kaluza and colleagues22 developed a widespread neurologic deficit 3 years after orchiectomy for seminoma. At autopsy, he had evidence of widespread neuronal loss as well as multifocal demyelination. IgG was found within the cytoplasm of the Purkinje cell neurons. Plotkin and colleagues24 described a 37-year-old man with an enhancing lesion in the left middle cerebellar peduncle that resolved with corticosteroid treatment. Systemic workup revealed a seminoma. In none of these patients were paraneoplastic antibodies found (in some they were not searched for). It is possible that the demyelinating lesions were manifestations of tumefactive multiple sclerosis or some other coincidental lesion (there does not appear to be an increased risk of cancer in patients with multiple sclerosis, with the possible exception of breast cancer25), but the significant number with an uncommon cancer such as seminoma suggests that they are probably paraneoplastic.

Figure 4–4. Paraneoplastic demyelination associated with a seminoma. A. MRI of the brain identifies a well-demarcated area of increased signal involving both occipital lobes and the corpus callosum. The cerebral cortex is completely spared. B. Histology of the brain biopsy. Myelin and axial are preserved in a normal brain (upper left). In the pathologic area (lower right), myelin is lost, but axons are preserved. (From Jaster JH, Bertorini TE, Dohan FC, Jr., et al. Solitary focal demyelination in the brain as a paraneoplastic disorder. Med Pediatr Oncol. 1996;26:111–115,19 with permission.)

Figure 4–4.
Paraneoplastic demyelination associated with a seminoma. A. MRI of the brain identifies a well-demarcated area of increased signal involving both occipital lobes and the corpus callosum. The cerebral cortex is completely spared. B. Histology of the brain biopsy. Myelin and axial are preserved in a normal brain (upper left). In the pathologic area (lower right), myelin is lost, but axons are preserved. (From Jaster JH, Bertorini TE, Dohan FC, Jr., et al. Solitary focal demyelination in the brain as a paraneoplastic disorder. Med Pediatr Oncol. 1996;26:111–115,19 with permission.)

Other reports are less convincing. Some have suggested that lymphoma may present as paraneoplastic demyelination.26–29 These cases almost certainly represented brain lymphoma treated with corticosteroids that abolished the tumor cells before the biopsy was performed.29

A patient with myeloma presented with an acute disseminated encephalomyelitis.21 The lesions regressed after treatment of the myeloma, which included corticosteroids. A second patient who died with a monoclonal IgM kappa gammopathy was found to have extensive demyelination in the brain, brainstem, and spinal cord.30 The significance of these two cases is unclear. Summerfield and colleagues31 have reported a 75-year-old woman with a recent history of confusion and falls associated with multifocal white matter changes and oligoclonal bands in cerebrospinal fluid (CSF). Workup revealed SCLC. The authors considered this patient to be an instance of SCLC presenting with acute disseminated encephalomyelitis. What the white matter lesions actually represented in a 75-year-old woman is unclear. We conclude that paraneoplastic demyelination probably occurs with seminoma, but may be coincidental in other cancers.

A single case of Marchiafava-Bignami disease associated with ovarian cancer has been reported as a paraneoplastic syndrome.32 This usually nutritional disorder is characterized by demyelination in the corpus callosum and sometimes other structures in the brain and brainstem. We have seen a similar case in a patient with pancreatic cancer receiving chemotherapy that we attributed to malnutrition.

PATIENT 4–3

A 54-year-old woman was discovered to have carcinoma of the pancreas in May of 2007. She was treated with neoadjuvant chemotherapy, radiation therapy, and surgery in November of 2007. In July 2008, a lung metastasis was discovered, and she was started on a protocol including gemcitabine, erlotinib, and sorafenib. After the third treatment, she developed the sudden onset of pain and numbness in her feet and hands and, subsequently, slurred speech, difficulty walking, and generalized weakness. A lumbar puncture was performed that revealed no abnormalities. An MRI (Fig. 4–5) showed nonenhancing hyperintensity in the splenium of the corpus callosum and in the deep cerebellum. The radiologist raised the possibility of Wernicke's encephalopathy. However, a paraneoplastic syndrome was also considered, and she was treated with plasma exchange (number unknown). When examined 3 weeks later, she was markedly cachectic, having lost over 40 pounds. The central nervous system symptoms had rapidly recovered, but there was painful sensory loss to all modalities in all four extremities, to the knees in the lower extremities and the wrist in the upper extremities, making it difficult for her to walk (sensory ataxia) and use her hands for coordinated movements except under direct vision. Deep tendon reflexes were absent.

Figure 4–5. MRI of patient PATIENT 4–34–3. A. Demyelination in the splenium of the corpus callosum. B. Demyelination in the brachium pontis bilaterally.

Figure 4–5.
MRI of patient 4–3. A. Demyelination in the splenium of the corpus callosum. B. Demyelination in the brachium pontis bilaterally.

Comment

With the exception of sorafenib, which causes the hand-foot syndrome33 and sometimes a mild sensory neuropathy, there was nothing in her treatment that could explain the symptoms. However, she was so cachectic and the MRI so uncharacteristic of typical paraneoplastic syndromes that a nutritional disorder seemed more likely than a paraneoplastic disorder. The MRI was reminiscent of Marchiafava-Bignami disease, a demyelinating disorder said to be most common in red-wine alcoholics but in fact almost certainly a nutritional deficiency. Interestingly, a single case32 describes a patient with an almost identical MRI associated with ovarian cancer. The authors considered that their patient did suffer from Marchiafava-Bignami syndrome, probably paraneoplastic. It was not clear to us from the case report whether this patient was nutritionally deficient or not.

BLOOD VESSELS (VASCULITIS)

Blood vessels may occasionally be affected in paraneoplastic syndromes. Cerebral vasculitis may occur as part of a more diffuse systemic vasculitis or be restricted to the cerebral vasculature. Most reviews of cerebral vasculitis mention a paraneoplastic vasculitis.34, 35 The best documented cerebral vasculitis is a granulomatous angiitis affecting patients with Hodgkin disease. In 2000, Rosen and colleagues36 described such a patient and identified 12 other patients from the literature. Several patients have been reported since37–39 (Fig. 4–6).

Figure 4–6. A. Diffusion-weighted image showing multiple areas of restricted diffusion (arrow) diagnostic of cerebral infarction. B. Cerebral angiogram showing areas of focal constriction and dilatation (arrows) compatible with cerebral vasculitis.

Figure 4–6.
A. Diffusion-weighted image showing multiple areas of restricted diffusion (arrow) diagnostic of cerebral infarction. B. Cerebral angiogram showing areas of focal constriction and dilatation (arrows) compatible with cerebral vasculitis.

Cerebral vasculitis may either occur in patients with established Hodgkin disease or precede identification of the cancer. The patient usually presents with headache, nausea and vomiting, or neurologic signs that may be multifocal. Generalized convulsions may also herald the onset of the disease. Characteristically, the MRI shows evidence of multifocal infarction in the brain. In several cases the MRI resembled reversible posterior leukoencephalopathy (PRES) (see also p. [link]).38 (That disorder, characterized by T2 hyperintensity in the distribution of posterior cerebral arteries, results from endothelial damage as occurs in hypertensive encephalopathy or damage induced by drugs such as cyclosporine.) Cerebral angiograms or magnetic resonance angiograms (MRA) may show multiple areas of constriction in blood vessels, a finding that can also be found in patients with nonbacterial thrombotic endocarditis.40 Unfortunately, angiography is often negative when the involved vessels are too small to be seen angiographically. The diagnosis can usually be established by biopsy, but because not all vessels are involved, the biopsy may be negative. Most patients respond to immunosuppression with drugs such as corticosteroids and cyclophosphamide,39 although not all patients make a full recovery. Sometimes, the neurologic illness is fatal. One unusual patient suffered recurrent symptomatic cerebral venous thrombosis, unresponsive to anticoagulant therapy. Although probably not symptomatic, there was evidence of arterial narrowing on angiography. The neurologic disorder led to a diagnosis of Hodgkin disease. Immunotherapy with corticosteroids and rituximab led to a dramatic recovery.41

PATIENT 4–4

A 59-year-old man suffered chronic lymphocytic leukemia, first diagnosed in 1999 on a routine blood count. The illness was complicated by an autoimmune cytopenia. He was treated with pentostatin, cyclophosphamide, and rituximab, therapy which was completed in October 2005. The patient's wife reported that after the first application of chemotherapy, his memory declined and never returned to normal, although he was fully functional. In February 2009 he became acutelydisoriented, suffering visual hallucinations and what appeared to be a dressing apraxia. A lumbar puncture contained 16 white cells but was otherwise normal. An MRI early in April 2009 revealed multiple areas of restricted diffusion, compatible with subacute cerebral infarcts (Fig. 4–6A). A cerebral angiogram performed several days later gave evidence of multiple intermittent segments of smooth widening and narrowing of cortical vessels in all vascular territories (Fig. 4–6B), compatible with a cerebral vasculitis. There was no evidence of systemic vasculitis. A transesophageal echocardiogram was normal. Paraneoplastic antibodies were negative.

Examination in April 2009 revealed poor cognitive functions characterized by disorientation to time and place, a poor attention span, and poor recent memory. The segmental neurologic examination was otherwise normal. Treatment was begun with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) with a remarkable response in his neurologic state. When evaluated in October, his Mini-Mental Status Examination had improved from 11/30 to 27/30, with only minor complaints of memory loss. An MRI revealed normalization of the previously seen FLAIR abnormalities. A chronic infarct of small size was found in the right parietal lobe. He remains clinically well.

Comment

The relatively sudden onset in February of neurologic disability that suggested multifocal disease, along with the mild pleocytosis in the spinal fluid, and the MRI evidence of multiple small infarcts strongly support the diagnosis of cerebral vasculitis. The absence of a paraneoplastic antibody did not rule out a paraneoplastic vasculitis. The substantial improvement following treatment of the underlying neoplasm supports the diagnosis of a paraneoplastic syndrome.

The pathogenesis of granulomatous angiitis complicating Hodgkin disease is unknown. Varicella zoster virus infecting the vasculature has been implicated, but in some patients no evidence of zoster infection can be found.42

Other forms of paraneoplastic vasculitis are much rarer and some may be coincidental. Liozon and colleagues43 examined 271 consecutive patients with giant-cell arteritis (cranial arteritis/temporal arteritis), retrospectively analyzing the frequency of malignancy occurring within a year either before or after a vasculitis. They found 20 patients (7.3%) and reviewed 27 cases from the literature. There were no patients with Hodgkin disease; eight had other hematologic malignancies, and the others patients had various solid tumors. Hutson and colleagues44 reviewed the experience at the Cleveland Clinic. They identified 2800 patients with vasculitis, over 69,000 patients with cancer, and 69 patients with both over an 18½ year period. They found 12 patients in whom both vasculitis and cancer occurred within the same 12 months; 7 of these patients were cutaneous vasculitides, 2 were giant-cell arteritis, 2 were polyarteritis nodosa, and 1 was Wegener's granulomatosis. Six patients had hematologic tumors and the other patients had various solid tumors. It is not clear whether any of the lymphomas were Hodgkin lymphoma. The authors concluded that “in rare instances, vasculitis may be a presenting manifestation of malignancy.” They did not think that all patients with vasculitis needed to be evaluated for cancer, but suggested that in patients with a poor response to usually effective therapy, cancer should be considered.

PATIENT 4–5

A 43-year-old man was in excellent health until May of 1997 when he suddenly developed weakness of his left arm. He was admitted to the hospital where CT and MRI of the brain were negative, as were carotid Doppler imaging and an echocardiogram. His platelet count was 700,000. Initially, this was believed to be a secondary thrombocytosis, but workup eventually revealed essential thrombocytosis, and he was treated with hydroxyurea. Despite treatment, the patient continued to have episodic changes in neurologic function and eventually workup showed evidence of multiple infarcts. A cerebral angiogram, however, was negative. Despite treatment, cerebral infarcts continued to appear; he then developed pneumonia and died 4 years after the onset of symptoms.

At autopsy, severe vascular abnormalities were found involving leptomeningeal arteries that were believed responsible for multiple infarcts about the brain. There were similar vascular changes in the pancreas and prostate. He also had a focal subendocardial infarct.

Comment

There was initial speculation that the transient ischemic attacks were related to thrombotic occlusion of blood vessels. However, this disorder rarely occurs at platelet counts below 1 million, a level he never reached. Instead, the final diagnosis was cerebral vasculitis (with minimal evidence of vasculitis elsewhere in the body) as a paraneoplastic syndrome related to essential thrombocytosis.

HIPPOCAMPUS (LIMBIC ENCEPHALITIS/ENCEPHALOPATHY)

History

The most common paraneoplastic disorder affecting the cerebral hemispheres is limbic encephalopathy.45–48 The clinical characteristics include loss of short-term memory, complex partial (temporal lobe) seizures, and behavioral abnormalities (Table 4–2).

Table 4–2 Clinical Features in 50 Patients with Limbic Encephalitis

Symptom

Patients (n)

Loss of short-term memory

42

Seizures

25

Temporal lobe, “psychomotor”*

10

Generalized only

6

Mixture

9

Acute confusional state

23

Behavioral abnormalities

21

Affective changes

7

Hallucinations

5

Disinhibition and personality changes

3

Mixed

6

*Orgasmic seizure.61

Data from Gultekin et al.48

The syndrome may arise either as an isolated phenomenon or as part of a more widespread encephalomyelitis, in particular, as part of the anti-Hu syndrome.49

Although isolated case reports had been published previously, in 1960 Brierley and colleagues50 identified the disorder as a clinical and pathologic syndrome, calling the disorder “subacute encephalitis of later adult life mainly affecting the limbic areas.” They described three patients, all middle-aged men, who over a few weeks developed behavioral changes including depression, agitation, and complex partial seizures. In two patients there was a mild pleocytosis; in the third the spinal fluid was entirely normal; all three died. At autopsy, one was found to have SCLC, a second to have “an encapsulated mass at the root of the right lung . . . [that] consists of fibrotic lymph nodes.” A third patient had only bronchitis. In all patients there were marked inflammatory changes in the medial temporal lobes and mild inflammation in other areas of the cerebral hemispheres and brainstem. The authors failed to connect the cancer to the neurologic syndrome. In fact, referring to the SCLC, they stated: “It seems most unlikely that this finding is in any way related to the encephalitis, but its occurrence should be noted.” We believe it is likely that the patient with the “fibrotic lymph nodes” had a spontaneously regressed SCLC.51 Eight years later, Corsellis (an author on the original paper) and colleagues52 recognized the association in an article titled “Limbic Encephalitis’ and Its Association with Carcinoma.” The authors presented three further cases and a review of the previous literature. They were able to find five patients reported after the original study. In only two of the studies was the disorder recognized to be paraneoplastic.53, 54 Although the term limbic encephalitis is the currently accepted, in some patients inflammatory changes are mild or even absent, so the term limbic encephalopathy also seems appropriate. Here the terms are used interchangeably.

Clinical Findings

The incidence of limbic encephalitis is unknown. When Croft and Wilkinson55 reported on neurologic findings in carcinomatous neuromyopathy, analyzing the findings in 1476 patients, they did not identify any patients with encephalopathy, even though they reported using the criteria of Brain and Adams that included encephalopathy (see Table 1–3). Dayan and colleagues56 compared the neurologic findings in patients with various histologic subtypes of lung cancer. Of 33 patients with SCLC,7 suffered from what they called “diffuse polioencephalopathy,” but that also included cerebellar degeneration. Of 200 patients with anti-Hu-associated paraneoplastic encephalomyelitis, 17 had limbic encephalitis as the predominant symptom.49 In a survey of 38 patients with paraneoplastic anti-Ma2-associated encephalitis, 7 suffered from limbic encephalitis without other accompanying deficits.57 Several other patients suffered from limbic encephalopathy as part of a more widespread encephalitis (see below).

Gulktekin and colleagues48 analyzed 50 patients with paraneoplastic limbic encephalitis and identified 137 other patients published in the English literature up to the year 2000. SCLC was the most common cancer causing the syndrome (40%), with testicular cancer next in frequency (20%). Almost all patients with anti-NMDA receptor encephalitis suffer from limbic encephalopathy, but almost always as part of a more widespread clinical disorder.58 Ovarian teratoma is the usual cause (see Chapter 13). Thus, limbic encephalitis is probably the most common paraneoplastic cerebral hemisphere syndrome. Its exact incidence is unknown and it is probably underestimated59; however, it is still rare.

Paraneoplastic limbic encephalitis usually begins rapidly with changes in mood and personality worsening over days to weeks.48 ccompanying the mood changes is severe impairment of recent memory with relatively preserved remote memory. Patients are often agitated and confused and suffer hallucinations and generalized or complex partial seizures.48, 60, 61 The symptoms can begin quite abruptly.

PATIENT 4–6

A 63-year-old woman, formerly a heavy smoker, was a partner in a catering service on Long Island. She seemed quite well when, one afternoon, she told her partner that she was feeling somewhat unwell and decided to go home early. Later that evening her car was found parked on the side of the Long Island Expressway. She was sitting in the car unable to give a history. She was taken to a psychiatric unit where she remained for several weeks, until it became apparent that her problem was severe memory loss, probably organic in nature. She was transferred to Memorial Sloan-Kettering Cancer Center. Her general physical and neurologic examinations were essentially negative, save for severe loss of recent and, to a lesser degree, remote memory. She was never able to tell us where she was or what the date was. She did not remember her catering business, but when asked about her occupation replied that she was a real estate agent, a job that she had had 5 years before. Aside from memory loss, her cognitive functions were entirely intact. Workup revealed imaging evidence of limbic encephalopathy and an anti-Hu antibody. During the course of her hospitalization she had cardiovascular collapse and died. Autopsy revealed SCLC in a mediastinal lymph node and severe diffuse encephalitis.

Alternately, the onset can be more gradual, occurring over several weeks or even a few months.

PATIENT 4–7

A 61-year-old woman who had smoked a pack and a half of cigarettes daily for many years began to note numbness and tingling beginning in her left foot in June 1992. Over the subsequent 3 months, the numbness progressed to involve the hands and feet symmetrically. By September she needed a cane to walk and by November was unable to walk without assistance. She recognized that the problem was that she was unable to discern the position of her feet. The same month, she noted numbness on the back of her neck. In October, her memory began to fail. Her family became concerned when she forgot that a brother-in-law to whom she had been quite close had died several months before. She lost track of what she was reading and had difficulty remembering TV shows that she had watched. She was believed to be both anxious and depressed. She was admitted to the hospital and noted to have several staring spells that lasted only a few seconds. A CT of the chest demonstrated an enlarged mediastinal node that on biopsy was nondiagnostic, showing only nonspecific inflammatory changes. When admitted to Memorial Sloan-Kettering, her cognitive functions were intact save for recent memory. She could not remember the flight to New York or the fact that she had a mediastinal biopsy. The remainder of the examination was marked by severe loss of sensation to all modalities, reaching the knees in the lower extremities and almost to the elbows in the upper extremities. There was also an area of decreased sensation in the neck. Strength was normal. A second mediastinal biopsy was performed and again showed nonspecific inflammation. An MRI demonstrated bilateral medial temporal hyperintensity with a small area of enhancement in the right temporal lobe (see Fig. 2–4). The anti-Hu antibody was positive. The suspicion that she had SCLC despite the two negative biopsies led us to prepare her for chemotherapy. Prior to administration of the drug, she had a cardiac arrest. She was placed on a respirator but was declared brain dead. At autopsy, SCLC was found in a single mediastinal node. The central nervous system was marked by inflammatory infiltrates throughout the brain and spinal cord. The anti- Hu antibody was identified in neurons.62

Comment

This patient with encephalomyelitis presented with asymmetrical sensory loss that eventually became asymmetrical. However, the focal sensory loss in the neck strongly suggested that the disorder was not a typical axonal neuropathy but instead probably a ganglionopathy. The memory loss and complex partial seizures heralded the onset of limbic encephalitis.

Loss of short-term memory with preservation of other cognitive function (what Carr named the “Ophelia syndrome”63) is a hallmark of the syndrome. Behavioral changes, ranging from depression through agitation to a florid delirium, are often present as well. Simple or complex partial seizures sometimes evolving into complex partial status epilepticus may be the major symptom. One of our patients continues, several years after apparent cure of SCLC, to have daily episodes in which he suddenly complains of being cold, appears to shiver, and repeats the phrase “Oh my God” over and over again (patient 4–8).

Alterations of consciousness range from acute confusional states with delusions and hallucinations to stupor or coma. Coma, often reversible, is characteristic of the ovarian teratoma (anti-NMDAR) syndrome (see patient 13–1).64 Behavioral abnormalities range from mild irritability through agitation or depression to frank psychosis in a few patients diagnosed as schizophrenic.

PATIENT 4–8

A 67-year-old asymptomatic man was discovered to have a left lung mass on routine CT of his chest (the CT was done as part of a clinical study). Biopsy revealed SCLC, and chemotherapy (cisplatin and etoposide) was begun. During his first chemotherapy session in March 2003, he developed tremor and fever, for which he was hospitalized. No infection was found, but he became very confused and agitated. Over the next several weeks he remained confused, was often agitated and depressed, and complained of poor memory. By May, his agitation was sufficiently severe that he required treatment with haloperidol, which made him somnolent. As of 2009, there has been no recurrence of the cancer but his neurologic disability continues. His recent memory was poor; there was some retrograde amnesia as well. He had forgotten the death of his father 5 years before the onset of his own illness. However, other cognitive function remained intact: Although he did not remember the month or year, he correctly answered that it was summer. When asked how he knew, he replied, because he was warm and wearing appropriate clothes for summer. He developed focal seizures characterized by the sudden onset of what appears to be shivering, during which he would sometimes complain of being cold, but generally simply repeat the words “oh my God” over and over during the 30–40 seconds of the episode. He usually has no memory of the episodes; at other times he can partially remember them; multiple anticonvulsants have failed to control these. Having formerly been a somewhat difficult man, he has become extremely angry and hostile toward his wife and seems agitated most of the time. He is still able to perform activities of daily living, including cooking and shopping, although he often refuses to do this. The MRI performed several months after the onset of symptoms revealed cerebral atrophy with subtle (even equivocal) hyperintensity changes in the medial temporal lobes on FLAIR images (Fig. 4–7). His serum contained an anti-Hu antibody that has persisted to the present.

About two-thirds of patients have clinical symptoms outside the limbic system.48 These may include cortical, hypothalamic, cerebellar, and brainstem dysfunction. In one series of 24 patients with paraneoplastic limbic encephalopathy, 12 out of 22 had clinical signs of other neurologic involvement.60

Figure 4–7. MRIs of patient PATIENT 4–84–8. A. The MRI performed several months after onset of symptoms reveals subtle hyperintensity in the medial temporal lobes (arrow). Such hyperintensity is difficult to interpret, as minor changes are often seen in normal individuals. Four years later while still symptomatic there is no significant change.

Figure 4–7.
MRIs of patient 4–8. A. The MRI performed several months after onset of symptoms reveals subtle hyperintensity in the medial temporal lobes (arrow). Such hyperintensity is difficult to interpret, as minor changes are often seen in normal individuals. Four years later while still symptomatic there is no significant change.

Laboratory Investigations

Diagnostic tests include CSF evaluation, MRI, measurement of autoantibodies, electroencephalogram (EEG), positron emission tomography (PET scan), and single photon emission computed tomography (SPECT scan) (Table 4–3). Table 4–4 illustrates the findings in 50 patients with the syndrome.

Table 4–3 Diagnostic Criteria of Limbic Encephalitis

  1. 1 Acute or subacute onset <3 months

  • Memory loss with preservation of other cognitive functions

  • Simple or complex seizures (temporal lobe)

  • Behavioral symptoms (agitation, depression)

  1. 2 Inflammatory CSF (∼20–30 cells)

  1. 3 EEG with temporal lobe slowing or seizures

  1. 4 MRI: hyperintensity of middle and temporal lobe(s) on FLAIR with or without enhancement

  1. 5 Hypermetabolic or hypometabolism PET (temporal lobe(s)

  1. 6 Antineuronal antibodies, e.g., anti-Hu, anti-Ma2, anti-NMDAR

Table 4–4 Diagnostic Tests in 50 Patients with Paraneoplastic Limbic Encephalitis

MRI

CSF

Paraneoplastic Antibodies

EEG

50 patients

Abnormal*: 28

Abnormal: 40

Positive: 30

Abnormal: 27

with PLE

Normal: 16

Normal: 9

(18 Hu, 10 Ta**, 2 Ma)

Normal: 6

Not available: 6

Not available: 1

Atypical: 4

Not obtained 17

(5 had CT study)

Negative: 16

*“Abnormal” indicates unilateral10 or bilateral15 temporal lobe abnormalities on T2-weighted sequences; in 5 of these 25 patients the lesions showed contrast enhancement. Three patients without temporal-limbic MRI findings had white matter abnormalities in other regions: 1 multifocal, 1 diffuse, and 1 perithalamic and deep white matter changes.

“Abnormal” indicates inflammatory changes, including increased proteins (24/47), pleocytosis (24/47), increased IgG synthesis (15/15), and oligoclonal bands (10/13).

**TA=Ma2

“Abnormal” indicates temporal epileptic focus (unilateral 10; bilateral 3), periodic lateralized epileptiform discharges, general nonspecific slowing, and abnormal but not specified.

From Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123:1481–1494,48 with permission.

The CSF is typically inflammatory, at least early in the course of the disease. The MRI may be normal, although abnormalities, particularly hyperintensity on the T2-weighted or FLAIR image, sometimes with contrast enhancement, are common48 (Fig. 2–4). At times the medial temporal lobe changes are more subtle (Fig. 4–7).

Electroencephalographic findings include focal or generalized slowing and occasional epileptiform activity, particularly in the temporal areas.60 Measurement of brain metabolism by either PET or SPECT shows abnormalities in the medial temporal lobes. The area may be either hypermetabolic, related to his seizure activity or inflammation,65, 66 or it may be hypometabolic, particularly late in the course related to neuronal degeneration (see Fig. 2–5B).67

Antibodies

The most important diagnostic test is measurement of paraneoplastic antibodies46, 48, 60 (Table 4–5).

Table 4–5 Antibodies in Limbic Encephalopathy*

Antibody

Published Cases

Frequency of Cancer

Usual Cancer

Anti-Hu

>200

>95%

SCLC

Anti-CRMP 5 (CV2)

∼50

>95%

SCLC, thymoma

Anti-amphiphysin

<50

>95%

SCLC

Anti-Ma2

∼100

>95%

Testis

Anti-NMDAR

∼100

8–58%

Ovarian teratoma

Anti-AMPAR

∼15

66%

SCLC, breast

Anti-GABA-BR

∼15

∼ 50%

SCLC

Anti-LGI1 (VGKC)

>50

<5%

Thymoma, SCLC

Anti-ADK5

2

0

None

Anti-GAD

>50

<1%

SCLC, colon

Anti-BRKSK2

1

100%

SCLC

*Some patients have more widespread encephalopathy, especially Anti-NMDAR and Anti-Ma2.

ADK5, adenylate kinase; BRKSK, BR serine/theronine kinase. See also Table 2–4.

Modified from a table suggested by Dr. Francesc Graus.

Anti-Hu antibodies are generally associated with encephalomyelitis in which limbic encephalitis may be the only symptom, the predominant symptom, or a minor symptom. The tumor is usually SCLC (Table 4–6), although in a series of 200 Anti-Hu patients, only 111 were SCLC; 15 were non-small cell lung cancer (NSCLC), 6 were prostate, and 6 were gastrointestinal, along with a scattering of others; 18 patients with probable lung cancer did not have histologic proof, and in 33 patients no tumor was identified.49 Anti-CRMP5 (CV2) is often associated with more widespread symptoms, including chorea, cerebellar ataxia, myelopathy, peripheral neuropathy, and optic neuropathy68; SCLC and thymoma are the common tumors. The anti-Ma proteins often cause hypothalamic and brainstem dysfunction as well as limbic encephalitis (see below). Testicular tumors are the most common cause; NSCLC can also be associated with the anti-Ma1 antibody.57 Anti-amphiphysin antibodies are found in patients with breast cancer as well as in those with SCLC. In addition to limbic encephalopathy, some patients often have stiff-person syndrome69 (see Chapter 6). Anti-NMDA receptor antibodies are associated with a rather severe encephalopathy and may result in coma (see patient 13–1). The symptoms are associated with ovarian teratomas (nonmalignant). The behavioral symptoms are striking, with many of the patients being admitted to psychiatric units before the diagnosis is discovered.58, 64 Appropriately treated, the disorder, even if resulting in coma, is often but not always reversible.64, 70

Table 4–6 Tumors Associated with Paraneoplastic Limbic Encephalitis

Type of Tumor

Current Series

(50 patients)

English Literature

(72 patients)

Lung cancer

25 (50%)

43 (59%)

SCLC

20 (40%)

39 (54%)

Non-SCLC

5 (10%)

3 (4%)

Atypical carcinoid tumor

1 (1%)

Testicular germ-cell tumors

10 (20%)

4 (6%)

Breast cancer

4 (8%)

2 (3%)

Hodgkin disease

2 (4%)

5 (7%)

Immature teratoma (ovary)

2 (4%)

2 (3%)

Thymoma

1 (2%)

5 (7%)

Other

4* (8%)

11 (15%)

Positive paraneoplastic—antibodies without identifiable tumor

2 (4%)

*Includes 1 adenocarcinoma of the colon, 1 adenocarcinoma of the ovary, 1 chronic myeloid leukemia, and 1 plasma cell dyscrasia.

Includes 3 adenocarcinomas of the colon, 2 carcinomas of the esophagus, 1 small-cell cancer of the ovary, 1 small-cell cancer of the prostate, 1 renal cancer, 1 cancer of the bladder, 1 neuroblastoma, and 1 mediastinal germ cell tumor (1 patient included in the group of SCLC also had a renal cell cancer).

One patient had anti-Hu antibodies and the other had anti-Ma antibodies.

SCLC, small-cell lung cancer.

From Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123:1481–1494,48 with permission.

Antibodies to LGI1 cause autoimmune limbic encephalopathy that is usually nonparaneoplastic but may sometimes be paraneoplastic, associated with carcinoma or thymoma.71 The disorder, first described by Vincent and colleagues in 2004,72 (originally attributed by them to antibodies against voltage-gated potassium channels, but the recent studies indicate are actually antibodies against LGI173) is being increasingly recognized. The disorder is usually responsive to immune suppression (see Chapter 13). However, see patient 1–2.

Paraneoplastic limbic encephalopathy can also occur in the absence of identifiable autoantibodies. Particularly important in this respect is the disorder associated with Hodgkin disease (Ophilia syndrome63).67, 74 Recent evidence from Dr. Dalmau's laboratory has identified an antibody to neuronal cell surfaces that is not yet fully characterized (Dr. Josep Dalmau, personal communication). Neurologic symptoms usually precede discovery of the tumor.

Differential Diagnosis

Perhaps the most important alternate diagnosis to consider is herpes simplex encephalitis75 (Table 4–7).

Table 4–7 Differential Diagnosis of Limbic Encephalopathy

Disorder

Reference

Herpes simplex encephalitis

75

Other encephalitis (e.g., HHV-6)

77

Glioblastoma

126

Systemic lupus

127

Hashimoto thyroiditis

128

Sjögren syndrome

129

Antiphospholipid syndrome

130

CNS vasculitis

131

4-aminopyridine toxicity

132

Neurosyphilis

80

Genetic lymphoproliferative disorder

81

Parkinsonism

1

Modified from Tuzun and Dalmau.46

Herpes simplex encephalitis is more common than paraneoplastic limbic encephalitis (1 in 250,000 vs 1 in 500,000 individuals per year). The clinical picture can be identical, but headache, fever, and generalized convulsions aremore common in herpes simplex than in paraneoplastic limbic encephalitis. The disease is more likely to be unilateral at onset, have red cells as well as white cells in the spinal fluid, and to show hemorrhagic changes on MRI. The diagnosis is established by identifying viral DNA (PCR) in spinal fluid. Generally speaking, all patients in whom this viral infection is a diagnostic consideration should be treated with antiviral agents until a definitive diagnosis is established. Other viral infections, in particular other herpes viruses,76 especially HHV-6,77 can occasionally mimic limbic encephalitis. We have encountered several patients in whom the acute onset of generalized or temporal lobe seizures with MRI abnormalities in the temporal lobe were thought to be due to either herpes or paraneoplastic limbic encephalitis but instead turned out to be a result of a nonenhancing brain tumor. Dr. Francesc Graus has informed us about a patient with a glioblastoma in whom bilateral medial temporal tumor mimicked the MRI of limbic encephalopathy. To complicate matters, the patient's LGI1 (VGKC) antibodies were borderline positive.

The other important diagnostic consideration is to differentiate paraneoplastic limbic encephalopathy from nonparaneoplastic autoimmune limbic encephalopathy.46, 78, 79 This disorder, clinically indistinguishable from paraneoplastic limbic encephalitis, is associated with different antibodies, the most common of which antibodies against LGI172 or, less commonly, CASPR273 (see Chapter 13). Although the disorder is usually not paraneoplastic, we believe that all patients require at least an initial search for an underlying neoplasm (see Chapter 2).

Rarely, neurosyphilis may closely mimic the clinical symptomatology, the MRI (hyperintensity in medial temporal lobes bilaterally), and the spinal fluid pleocytosis. However, CSF antibodies are those of syphilis and not paraneoplastic disorders.80 One patient with X-linked lymphoproliferative disease developed a limbic encephalopathy associated with bilateral medial temporal lesions that contrast enhanced. The patient had also had non-Hodgkin lymphoma several years previously, so whether the neurologic syndrome was paraneoplastic or caused by a genetic disorder is unclear.81

The other diagnostic considerations outlined in Table 4–7 rarely constitute a major problem. Parkinson's disease is an interesting problem. The classical signs of parkinsonism may, as indicated below, be paraneoplastic in origin. Although the overall incidence of cancer is lower in patients with Parkinson's disease,82 melanomas appear to be increased,83 and patients with parkinsonism caused by a mutation in the Park2 gene (mutation of this gene is the most frequent cause of autosomal recessive early-onset parkinsonism) appear to have an increased incidence of cancer, particularly glioblastoma and colon cancer.84

Pathology

Typical paraneoplastic limbic encephalopathy is characterized by destruction of hippocampal neurons along with inflammatory infiltrates, both in the perivascular spaces and in the parenchyma. Parenchymal infiltrates consist largely of T-cells; those in the perivascular spaces are a combination of B-cells and T-cells. Dalmau and colleagues have reported the presence of anti-Hu antibody in the parenchyma and cells of the hippocampus of patients dying with paraneoplastic encephalomyelitis62 (Fig. 3–5). A similar finding has been reported in a patient with anti-Ri encephalopathy.85 This finding suggests a major role for B-cells in the pathogenesis of the disorder (see below). In some patients, particularly those who die many years after the disorder begins, findings are consistent with sclerosis of the hippocampus, without inflammatory infiltrates,74 particularly in patients with Hodgkin disease. Whether inflammation was present at onset and disappeared over time, as happens with the CSF, is unclear. However, one report describes hypometabolism in the medial temporal lobe and evidence of hippocampal sclerosis within 6 months of the onset of clinical symptoms.67

Pathogenesis

As indicated in Chapter 3, the exact pathogenesis of limbic encephalitis, whether restricted to the hippocampus or associated with more widespread encephalomyelitis, is unknown. In anti-Hu limbic encephalitis, T-cells with a restricted T-cell receptor Vβ repertoire are found in CSF. In SCLC, they are found within the parenchyma of the brain itself.86

Treatment

Treatment is described in Chapter 2. In a few instances, patients with catatonic symptoms have responded to electroshock therapy. Both mediastinal germ cell tumors87 and ovarian teratomas88 have been reported to respond to that treatment.

HYPOTHALAMUS

Isolated paraneoplastic hypothalamic dysfunction is rare. The disorder usually occurs in conjunction with a more widespread encephalomyelitis, especially limbic89 or brainstem90 encephalitis (Chapter 5). Hypothalamic dysfunction characteristically occurs in patients with Ma-2 (Ta)-positive testicular cancer,57, 91, 92 CRMP 5 (CV2) encephalomyelitis associated with thymoma,93 and anti-NMDR receptor encephalomyelitis associated with ovarian teratomas.58 The disorder also occurs in children with neuroblastoma94 and sometimes in children without known cancer 95; the disorder is sometime responsive to immunoglobulin therapy.96 Symptoms of hypothalamic dysfunction include somnolence, temperature dysregulation, endocrinopathies (diabetes insipidus and hypothyroidism),48 hyperhidrosis, weight gain, and myokymia (Table 4–8).

Table 4–8 Some Clinical Findings: Hypothalamus

Finding

Reference

Narcolepsy or somnolence

133

Cataplexy or hypnagogic hallucinations

57, 134

Temperature dysregulation

48

Hyperhidrosis

Endocrinopathies

48

Diabetes insipidus

Hypothyroidism

Weight gain

89

Loss of libido

48

Narcolepsy as a symptom of hypothalamic dysfunction is associated with absence of hypocretin-1 in CSF, exactly as occurs in idiopathic narcolepsy.97 This suggests that the paraneoplastic disorder has destroyed the hypocretin-secreting cells.

The MRI may reveal abnormalities in the hypothalamus (Fig. 4–8) including contrast enhancement. Inflammatory lesions can be found in the hypothalamus. Treatment consists of discovery and treatment of the underlying tumor as well as immunosuppression (see Chapter 2). Patients with testicular cancer and anti-Ma2 antibodies have sometimes stabilized and even improved, at least partially.91 Patients harboring other antibodies, such as anti-Hu, do less well.

Figure 4–8. MRI from patient PATIENT 4–94–9. A. FLAIR image showing intense hyperintensity in the hypothalamus (arrow). The left medial temporal lobe also shows hyperintensity. B. The hypothalamic lesion enhances; there is less enhancement in the temporal lobe.

Figure 4–8.
MRI from patient 4–9. A. FLAIR image showing intense hyperintensity in the hypothalamus (arrow). The left medial temporal lobe also shows hyperintensity. B. The hypothalamic lesion enhances; there is less enhancement in the temporal lobe.

PATIENT 4–9

A 28-year-old man who had been previously reported on90 became confused, ataxic, and hypersomnolent in the course of 1 week. He had been successfully treated for stage I embryonal carcinoma 6 months earlier. An MRI revealed enhancing lesions in the hypothalamus as well as in the temporal lobe and brainstem (Fig. 4–8). An antibody previously uncharacterized, but subsequently identified as anti-Ma2, was found in the serum. A biopsy of the hypothalamus showed inflammation, neuronophagia, gliosis, and activated microglial cells His neurologic signs persisted despite no recurrence of the tumor.

Comment

This patient, patient 1 in a report by Bennett et al. in 1999,90 was the first patient reported with what was subsequently called the anti-Ma2 syndrome.92 His MRI showed the characteristic changes in both hypothalamus and brainstem as well as in the hippocampus. The antibody was identified by immunohistochemistry and Western blot and only later fully characterized.

BASAL GANGLIA AND THALAMUS

Symptoms affecting this portion of the anatomy are depicted in Table 4–9. As with hypothalamic dysfunction, symptoms generally occur as part of the widespread encephalomyelitis. Characteristic antibodies include anti-Hu, anti-Ma1, anti-Ma2, and CRMP 5. Chorea,98 often associated with either the NMDAR or CRMP 5 antibodies, is probably the most common manifestation of basal ganglia involvement. Vernino and colleagues99 described 16 patients with paraneoplastic chorea. In 11 patients it was the initial or the most prominent symptom. The responsible cancers included lung cancer, lymphoma, and renal cancer. Chorea and other dyskinetic movements are common manifestations of anti-NMDAR antibody encephalopathy.100

Table 4–9 Clinical Findings: Basal Ganglia and Thalamus

Finding

Reference

Chorea

99

Ballism

107

Dystonia

104

Somnolence (thalamus)

108

Behavioral Disorders

Abulia

135

Obsessive-compulsive disorder

136

Dementia

137

The MRI may demonstrate lesions in the basal ganglia that sometimes enhance.101 Inflammatory infiltrates can be found in the basal ganglia99; in one case in which inflammatory changes were restricted to the basal ganglia, marked neuronal loss was found in the caudate nuclei bilaterally.102

Four patients in Vernino et al.'s series improved with treatment of the tumor and two improved with immunosuppression. We have seen a few patients in whom chorea was an exclusive symptom and who did not respond to therapy.

PATIENT 4–10

A 27-year-old man developed rheumatoid arthritis at the age of 3 and was found to have common variable immunodeficiency. At age 8 he developed Hodgkin disease and was treated with chemotherapy, radiotherapy, and splenectomy. During a subsequent relapse, he received additional chemotherapy and then developed bilateral optic neuritis (we believe he suffered from bilateral optic neuritis that occasionally complicates aggressive chemotherapy103). Other than the visual loss, he was normal neurologically until age 27, when he developed the rapid onset of cognitive difficulties, involuntary movements of all four extremities, and hearing loss. On examination he was poorly responsive and febrile, with poor nutrition requiring tube feeding. When aroused, he clearly had poor memory, hearing loss, and continuous choreoathetotic movements of sufficient intensity to require extensive padding of the bed. The movements were undoubtedly partially responsible for his poor nutrition. MRI did not show abnormalities in the basal ganglia, although there were two small cerebellar infarcts. Lumbar puncture showed a mild pleocytosis. Paraneoplastic antibodies were not found.

Despite treatment with IVIg, his symptoms did not improve. Recurrent infections complicated his course and he eventually died. At autopsy, blood cultures were positive for several bacteria, and the cause of death was thought to be septic shock. Residual Hodgkin disease was found involving mediastinal lymph nodes. The brain and spinal cord had multiple areas of encephalomyelitis characterized by the formation of microglia/neuronophagia nodules and subcortical gray matter of both the brain and spinal cord. The findings were believed to be compatible with a paraneoplastic encephalomyelitis related to his Hodgkin disease.

Another prominent symptom of basal ganglia or upper midbrain (substantia nigra) dysfunction is parkinsonism.104 The disorder may appear as typical parkinsonism, although it is usually poorly responsive to L-dopa or dopamine agonists.104 The onset is usually quick, distinguishing the disorder from idiopathic parkinsonism. One of our patients, a 28-year-old man with a testicular tumor, developed full-blown parkinsonism over a 3-week period. Although the testicular tumor was successfully treated, the parkinsonism did not respond to treatment.

PATIENT 4–11

A 66-year-old man with diabetes, hypertension, and coronary artery disease presented to neurologic attention in November of 2008 with confusion, generalized seizures, and visual hallucinations. His wife had noted tremor beginning in the right hand and then extending to all four extremities a few months before the hospital admission. This was followed by sudden loss of memory and a general decrease in cognitive function. An MRI was normal. The seizures were controlled with anticonvulsants. A diagnosis of parkinsonism with dementia was made, and the patient was treated with a dopamine agonist with little effect. A physician suggested the possibility of a paraneoplastic syndrome and imaging revealed SCLC. He was started on chemotherapy and given IVIg with no effect on the neurologic disorder.

On examination he had profound loss of both short- and long-term memory with other cognitive functions relatively intact. There was severe parkinsonian tremor of his lips, both arms, and the right legs. Postural reflexes were poor. There was increased tone with cogwheeling and poor postural reflexes. A diagnosis of paraneoplastic parkinsonism was made, but response to antiparkinsonian drugs was minimal.

Other extremely rare basal ganglia and thalamic paraneoplastic syndromes include a case of progressive supranuclear palsy in a patient with B-cell lymphoma105 and obsessive-compulsive disorder, with pathologic changes in the caudate nucleus.106 Ballistic movements have also been described in a patient with renal cancer.107 A patient with pulmonary and gastric cancers became somnolent with behavioral abnormalities and was found to have lesions predominantly in the thalamus.108

COGNITIVE AND BEHAVIORAL ABNORMALITIES

Some patients with cancer demonstrate cognitive or behavioral abnormalities that are present either before the cancer is identified or before treatment is undertaken. A recent 10-year population-based study from Denmark examined the likelihood that a patient with a psychiatric disorder would develop cancer within a short time after the psychiatric disorder was identified.109 The authors found an increased incidence of patients with psychiatric illness developing cancer, particularly within the first month after the psychiatric diagnosis was made. The psychiatric disorders studied included “organic mental disorders,” psychotic disorders, mood disorders, anxiety disorders, and others. In some patients, such as those with brain tumors or brain metastases, the disorders were clearly not paraneoplastic. However, although data on MRI and neurologic workup are lacking, the incidence was increased in patients with other cancers, and the authors suggested these could be paraneoplastic.

Studies of women with breast cancer, men with testicular cancer and patients with SCLC in whom neuropsychological evaluation is done prior to treatment have suggested that many suffer from neurocognitive defects, compared with the incidence of such defects in the general population. For example, Wefel et al.110 found that 6/18 women with breast cancer who underwent a comprehensive neuropsychologic evaluation before treatment demonstrated cognitive impairment. In another study, 12% of 34 patients with node-negative breast cancer who received radiation but no chemotherapy exhibited neurocognitive dysfunction.111 Similar findings affect patients with SCLC. Grosshans et al. found that 43/93 (47%) of patients had evidence of impaired cognitive function before being treated with prophylactic cranial irradiation.112 Jim et al.113 performed neuropsychological evaluations on 187 women with early-stage breast cancer and compared the results with age-matched controls. Statistically significant differences in cognitive functioning were observed 6 months after treatment, regardless of whether the patients received chemotherapy or only radiation (not to the brain). Although there were no significant differences between cancer patients and controls with respect to cognitive symptoms, small but significant differences in memory and attention occurred in the breast cancer patients regardless of whether they received chemotherapy or not.

A recent report113A found that 46% of men with newly diagnosed nonseminomatous germ cell testicular cancer, after surgery, but before chemotherapy, exhibited cognitive impairment greater than expected from normal population. Impairment involved motor function, verbal learning and executive function.

Whether the cognitive abnormalities described in the above paragraphs are truly paraneoplastic is certainly not established, but the findings are intriguing. Whatever the cause, a recent report114 demonstrated that modafinil improved speed of memory and quality of episodic memory in patients with breast cancer who complained of fatigue.

Florid behavior abnormalities, including delirium, catatonia, and paranoia, can complicatelimbic encephalopathy. These abnormalities are particularly likely to occur in younger people with seminoma or ovarian teratoma. Delirium is a common symptom in patients with advanced cancer.115 A 91-year-old man without a history of psychiatric illness developed acute mania as the first symptom of a pancreatic tumor.116

Depression

Depression is common in patients with cancer.117 Various studies suggest a prevalence of 0%-38% for major depression and 0%-58% for depressive symptoms.117 Furthermore, the prevalence of depression varies with the nature of the underlying cancer. The disorder is more common with oropharyngeal, pancreatic, breast, and lung cancers and less common in colon and gynecologic cancers and lymphoma. The diagnosis may be difficult, because many of the symptoms that suggest depression in the cancer population, such as sleep problems, pain, weight loss, and cognitive impairment, are present in patients with cancer but no depression. The major manifestations of depression are often ignored by the physician because the physician believes that such symptoms are to be expected in any patient with cancer. This is not true; most patients with cancer are not depressed.

Depression and minor cognitive abnormalities have not generally been considered to be paraneoplastic. However, depression sometimes precedes the discovery of the cancer and is present in the absence of other somatic symptoms such as pain that may cause psychologic distress. This phenomenon is particularly prominent in pancreatic cancer;118, 119 in one study, 76% of patients with pancreatic cancer demonstrated depressive symptoms prior to the diagnosis. This differed from the 20% of patients with colon cancer who had such symptoms.120

The pathogenesis of depression either preceding a cancer or occurring during the course of the cancer is probably multifactorial. Recent evidence suggests that cytokines produced by cancers may play an important role121, 122 (Fig. 4–9). A recent study in experimental animals with rat mammary carcinoma demonstrated evidence of depression and anxiety-like behaviors without other evidence of illness. Pro-inflammatory cytokines known to induce depressive-like behaviors, including IL-1β, IL-6, TNF-α and IL-10, were elevated in the periphery and the hippocampus in these rats.123 Furthermore, circulating corticosterone levels that might have inhibited cytokines were suppressed and gene expression of hippocampal glucocorticoid receptors was elevated. These results, as well as clinical studies in patients with known cancer,122 suggest that the combination of cytokine production and hypothalamic–pituitary–adrenal axis suppression may cause depression in patients with cancer, and the symptoms of depression may precede identification of the cancer.

Figure 4–9. A. Proposed mechanism of depression in patients with pancreatic cancer. (From Makrilia N, Indeck B, Syrigos K, Saif MW. Depression and pancreatic cancer: a poorly understood link. JOP. 2009;10:69–76,118 with permission.) B. Various aspects of being diagnosed with and tested for cancer activate inflammation through tissue damage and destruction and psychological stress. Cytokines of the innate immune response along with lifestyle changes, pain, and other consequences of cancer and its treatment alter the sleep–wake cycle, which in turn contributes to disruption of the neuroendocrine system, in particular, the hypothalamic–pituitary–adrenal (HPA) axis. Given the role of the HPA and glucocorticoids in regulating inflammatory responses, altered HPA axis function may disrupt glucocorticoid-mediated negative regulation of inflammation. Unrestrained inflammation and the associated increased release of pro-inflammatory cytokines, in turn, interact with CNS pathways that regulate behavior, leading to pathophysiologic changes that underlie depression, fatigue, impaired sleep, and cognitive dysfunction. CRH, corticotropin-releasing hormone; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kappa. (From Miller AH, Ancoli-Israel S, Bower JE, Capuron L, Irwin MR. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol. 2008;26:971–982,122 with permission.)

Figure 4–9.
A. Proposed mechanism of depression in patients with pancreatic cancer. (From Makrilia N, Indeck B, Syrigos K, Saif MW. Depression and pancreatic cancer: a poorly understood link. JOP. 2009;10:69–76,118 with permission.) B. Various aspects of being diagnosed with and tested for cancer activate inflammation through tissue damage and destruction and psychological stress. Cytokines of the innate immune response along with lifestyle changes, pain, and other consequences of cancer and its treatment alter the sleep–wake cycle, which in turn contributes to disruption of the neuroendocrine system, in particular, the hypothalamic–pituitary–adrenal (HPA) axis. Given the role of the HPA and glucocorticoids in regulating inflammatory responses, altered HPA axis function may disrupt glucocorticoid-mediated negative regulation of inflammation. Unrestrained inflammation and the associated increased release of pro-inflammatory cytokines, in turn, interact with CNS pathways that regulate behavior, leading to pathophysiologic changes that underlie depression, fatigue, impaired sleep, and cognitive dysfunction. CRH, corticotropin-releasing hormone; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kappa. (From Miller AH, Ancoli-Israel S, Bower JE, Capuron L, Irwin MR. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol. 2008;26:971–982,122 with permission.)

Patients with depression related to cancer often respond quite well to psychotropic drugs used to treat depression. They may also respond to treatment of the underlying tumor as well as to cytokine suppression122 (Fig. 4–10).

Figure 4–10. A. Algorithm for treatment of pancreatic cancer and depression. (From Makrilia N, Indeck B, Syrigos K, Saif MW. Depression and pancreatic cancer: a poorly understood link. JOP. 2009;10:69–76,118 with permission.) B. Treatment strategies for cancer-related symptoms. Sites for the implementation of treatments directed at the sickness response circuit are as follows: (1) immunologic treatments (such as soluble receptors of TNF-α and IL-1 receptor antagonists) that are designed to inhibit cytokine signaling directly, or treatments that block downstream mediators of inflammation, including prostaglandins, nitric oxide, and substance P; (2) neurobiologic treatments that target central nervous system (CNS) mediators of behavioral alterations including the monoamines and corticotropin-releasing hormone (CRH); (3) symptomatic treatments (such as narcotics for alleviation of pain, stimulants to combat fatigue, antidepressants for relief from depression) that address the ultimate manifestations of upstream mediators; and (4) treatments designed to take advantage of the normal endogenous feedback circuits that limit sickness responses in settings such as viral illness. COX, cyclooxygenase; NOS, nitric oxide synthase. (From Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. 2003;97:2919–2925,121 with permission.)

Figure 4–10.
A. Algorithm for treatment of pancreatic cancer and depression. (From Makrilia N, Indeck B, Syrigos K, Saif MW. Depression and pancreatic cancer: a poorly understood link. JOP. 2009;10:69–76,118 with permission.) B. Treatment strategies for cancer-related symptoms. Sites for the implementation of treatments directed at the sickness response circuit are as follows: (1) immunologic treatments (such as soluble receptors of TNF-α and IL-1 receptor antagonists) that are designed to inhibit cytokine signaling directly, or treatments that block downstream mediators of inflammation, including prostaglandins, nitric oxide, and substance P; (2) neurobiologic treatments that target central nervous system (CNS) mediators of behavioral alterations including the monoamines and corticotropin-releasing hormone (CRH); (3) symptomatic treatments (such as narcotics for alleviation of pain, stimulants to combat fatigue, antidepressants for relief from depression) that address the ultimate manifestations of upstream mediators; and (4) treatments designed to take advantage of the normal endogenous feedback circuits that limit sickness responses in settings such as viral illness. COX, cyclooxygenase; NOS, nitric oxide synthase. (From Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. 2003;97:2919–2925,121 with permission.)

ENCEPHALOMYELITIS

In 1965, Henson, Hoffman, and Urich1 described a series of patients with inflammation in various parts of the nervous system that were associated with cancer. That report included10 patients, some previously reported, mostly with lung cancer, who at autopsy had inflammatory lesions in several areas of the nervous system. They coined the term “encephalomyelitis with carcinoma” for the clinical and pathologic disorder that they believed resulted from an opportunistic viral infection. By 1982, Henson and Urich124 described the distribution of lesions in 39 patients with encephalomyelitis and malignant disease. They also included 11 patients with “pure sensory neuropathy” (see Chapter 8). They indicated that “the distribution of lesions is variable and tends to predominate, or even occur exclusively in one particular part of the nervous system, which can be somewhat arbitrarily split into five compartments.” Their subclassification (Table 4–10) is basically the one used in the description in the preceding paragraphs of this chapter.

Table 4–10 Clinical Classification of “Encephalomyelitis with Carcinoma”

Limbic encephalitis

Bulbar encephalitis

Cerebellar encephalitis

Myelitis

Ganglioradiculitis

Data from Henson1.

Only limbic encephalopathy, paraneoplastic cerebellar degeneration (Chapter 5), and sensory neuronopathy (Chapter 8) are likely to occur in isolation. The other disorders are more commonly found as part of a more widespread disorder that may involve not only the brain but also the brainstem, cerebellum, spinal cord, and even peripheral structures such as dorsal root ganglia, peripheral nerves, and even muscle.125 Occasionally, a patient will present with an isolated brain disorder other than limbic encephalopathy; examples are isolated Parkinson's disease and chorea, as described earlier. For an example of an extremely widespread encephalomyelitis, see patient 5–5 in the next chapter.

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