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Keywords:

  • Hypothalamus hamartoma;
  • Gelastic seizures;
  • Precocious puberty;
  • Stereotactic thermocoagulation

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary: Purpose: Hamartomas of the hypothalamus (HH) cause an uncommon and unusual epilepsy syndrome. The condition is recognized to affect children, but the presentation in adults is not well understood. We present 19 children and adult patients with HH, including three patients whose epilepsy began in adult life. The patterns of clinical presentation, evolution of the epilepsy from childhood to adult life, and electroclinical diagnostic features are presented.

Methods: Nineteen patients, both children and adults with HH and epilepsy, were evaluated clinically, with EEG, video-EEG, and magnetic resonance imaging (MRI) scanning. Seven patients underwent surgical resection of the hamartoma. Stereotactic thermocoagulation of the hamartoma was performed in two patients.

Results: Gelastic seizures occurred at onset of epilepsy in 15 of 16 early-onset cases. Subsequently, multiple seizures types occurred, which then evolved to mainly partial epilepsy with tonic or complex partial seizures (five of eight adults), or became entrenched symptomatic generalized epilepsy with atypical absences, drop attacks, and secondarily generalized seizures, and cognitive impairment (three of eight adults). In the adult-onset patients, gelastic seizures were not prominent, the epilepsy was milder, and they functioned normally. Stereotactic thermocoagulation of the hamartoma resulted in improvement in seizure control in two patients.

Conclusions: Gelastic seizures are not a prominent feature of epilepsy in adult patients with HH. The epilepsy associated with HH, although severe at onset, can evolve into a milder syndrome in later life. For less severely affected patients, minimally invasive alternatives to the traditionally difficult open surgical treatment should be considered.

Hamartomas of the hypothalamus (HHs) cause an epilepsy syndrome associated with gelastic seizures, precocious puberty (PP), and multiple seizure types (1,2). It is generally recognized to begin in childhood. The hamartomas are intrinsically epileptogenic (3,4), and ablation of the hamartoma by surgical and other means has been shown to cause seizure remission (5,6).

The pathophysiology of the epilepsy associated with the hamartoma is yet to be elucidated. It has been demonstrated by depth electrode studies that the gelastic seizures arise from the hamartoma (3,7). Ictal single-photon emission computed tomography (SPECT) studies have shown increased blood flow in the hamartoma during gelastic seizures (4). The origin of the other seizure types that occur is less clear. However, because all seizure types are reduced by the ablation of the lesion, the hamartoma clearly also has a fundamental role in the genesis of all the seizures.

In children, HHs can be associated with a devastating epilepsy syndrome, often compounded by additional severe behavioral problems and cognitive impairment. PP occurs in up to a third of patients (2). This is, however, only one end of a spectrum. The onset in adults is not well studied, and the milder presentation has been only recently recognized (8,9). We present the clinical and electroencephalographic features of 19 patients, both children and adults with HHs, who demonstrated a wider spectrum of disease, and we emphasize the clinical features noted in adult patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Nineteen patients were assessed at King's College and the Maudsley Hospital, London between 1991 and 2001. Their clinical data, scalp EEG recordings, and where available, video-EEG and depth electrode EEG recordings were reviewed. Magnetic resonance imaging (MRI) scans were evaluated for signal characteristics, size, location, and the nature of the attachment of the hamartoma to the hypothalamus. The relation of the hamartoma to the hypothalamus was classified as pedunculated (when the hamartoma was attached to the hypothalamus by a stalk) and sessile (broad attachment to hypothalamus) (10). Further they also were classified along the lines suggested by Arita et al. (11) as “parahypothalamic type” and “intrahypothalamic type.” Clinical correlation between the HH types and the epilepsy features was performed by using the Arita classification. Seven patients underwent surgical removal of the hamartoma, and these specimens were evaluated histopathologically. Two patients underwent stereotactic thermocoagulation of the HHs.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Patients

The patients were divided into two groups according to age at onset of the epilepsy. The purpose of classifying the patients in this manner was to highlight the differences in the severity of the epilepsy and cognitive and behavior changes between the early- and late-onset cases, and to demonstrate how the epilepsy evolved after early onset and progressed into adult life.

General aspects of the epilepsy

With the exception of one patient (patient 17 fromTable 1), all patients had, at present or in the past, severe epilepsy, with two to five seizure types. These included gelastic seizures (16 patients); atypical absences (nine patients); drop attacks (five patients); partial motor (four patients); brief, mainly sleep-related tonic seizures (seven patients); complex partial seizures of temporal lobe type (11 patients); and generalized convulsions (eight patients). Gelastic seizures were the first seizure type to manifest in all but two of the HH patients with early-onset epilepsy (group 1), and none of the adult-onset patients (group 2). A family history of epilepsy was not present in any of the patients.

Table 1. Electroclinical features of 19 patients with hypothalamic hamartoma
Patient number, age (yr)Onset, sz type (yr)PP onset (yr)Other sz typesLDMRI size (cm)InterventionResultEEG interictal spikesEEG ictal
  1. Gel, gelastic seizure; Sl, slowed background; C, complex partial seizures; Temp, temporal; T, tonic seizure; Fr, frontal; A, atypical absence; Pr, parasagittal; S, secondarily generalized seizure; Syl, sylvian; At, atonic seizure; GSW, generalized spike–wave; Pm, partial motor seizure; EGFRA, evolving generalized rhythmic fast activity; Mi, mild learning difficulty; SSW, slow spike–wave; Mo, moderate learning difficulty; N, normal; SD, severe learning difficulty; B, borderline learning difficulty; ND, not done; s, sessile; sz, seizure; SR, surgical resection of hamartoma; AEDs, antiepileptic drugs; GK, gamma knife treatment; STC, stereotactic thermocoagulation; IH, intrahypothalamic; PH, parahypothalamic; p, pedunculated; TL, temporal lobectomy; VNS, vagal nerve stimulator.

Group 1a         
1, 7Gel (1)C, T, A, SMo1.5, s, IHAEDs, SRGoodTemp, GSWND
2, 4Gel (2)7A, CMo2, s, IHAEDs, SRGoodTempND
3, 4Gel (0) 1.5S, AMo1, s, IHAEDs, SR, GKPoorFr, Temp, PrFr
4, 2Gel (1.5) 1.5C, At, PmMo3, s, IHAEDs, SRPoorFr, Temp, PrND
5, 8Gel (2)C, A, TSD1, s, IHAEDs, SRPoorTemp, SylEGRFA, SSW
6, 16Gel (1.5)CB2, s, PHAEDsGoodTempND
7, 5Gel (0)C, T, SMi1.5, s, PHAEDs, SRGoodFr, Temp, GSWND
Group 1b         
8, 16C (13)7C, S, A, TB1, p, PHAEDsPoorTemp, FrEGRFA, SSW, Fr
9, 54Gel (1)9A, T, SMi2, s, IHAEDs, VNSPoorTempND
10, 28Gel (5)CB1, s, IHAEDs, TLPoorTempTemp
11, 34Gel (3)A, At, SNot tested1, s, IHAEDs, SR, VNSPoorTemp, GSWND
12, 40Gel (0.5)T, At, A, SB1.5, s, IHAEDs, STCGoodTemp, Fr, GSWEGFRA, SSW
13, 24Infantile spasms (1.5)C, GelN1.5, s, IHAEDsGoodTempND
14, 42Gel (7)Pm, SB1, s, IHAEDsGoodFr, GSWEGFRA, SSW
15, 30Gel (1)T, SLow average0.5, s, IHAEDs, TL, STCGoodTemp, FrTemp
16, 41Gel (5)CN1, s, IHAEDsGood ND
Group 2         
17, 33Drop attacks8AN0.4, p, PHAEDGoodTempND
18, 52Gen szGel, CN1, s, IHAEDsGoodTempND
19, 55CSN1, p, PHAEDsGoodTempND

Of the seven patients who had open surgical resection of the HH, the surgical results and outcome of six patients have been published separately. Patients 1 through 5, and 11, from Table 1, have been previously reported in a multicenter study of surgical results in HHs (12). Two patients had stereotactic thermocoagulation of the HHs with good results and are discussed later. Standard outcome measures for the different medical and surgical treatments could not be used because of the presence of multiple seizure types. Hence the outcome measures used previously by Oguni et al. (13) for the treatment of intractable epilepsy were applied (i.e., seizure control was defined as good if there was >75% reduction in the predominant seizure type) (13). One patient had a vagus nerve stimulator (VNS) with no significant benefit.

Group 1

This group consisted of eight children and eight adults with epilepsy and diagnosed to have the HHs between the ages of 2 and 54 years. The diagnosis was made in childhood in eight patients (group 1a), but in the other eight (group 1b), the diagnosis was delayed and made only in adult life.

The epilepsy began between 0 and 5 years (mean, 2.1 years) with gelastic seizures in 14 patients in this group. Subsequent seizure types occurred after a mean of 1.3 years (range, 0–5 years). In six of these patients, PP developed. Twelve patients had varying degrees of learning difficulty (Table 1), and seven patients, all children, had additional behavior problems. Patient 8 had no gelastic seizures but had PP at age 7 years, and atypical absences, tonic, and complex partial seizures developed at age 13 years. MRI scan was diagnostic in all. However, initial imaging in four patients, two with a 0.5-T MRI scan, and two with an initial CT scan, did not detect the lesion. The diagnosis was only made when a 1.5-T MRI scan was performed at a later date.

The eight older patients in this group were between 19 and 54 years (mean, 33 years) at the time of diagnosis of the HH. Although gelastic seizures were initially present in all patients in this group (onset between 0.5 and 11 years; mean, 4.4 years), they completely disappeared in adolescence and young adulthood in two patients and were reduced to mere “feelings of an urge to laugh” in a further two patients. When the gelastic seizure was the presenting seizure type, a latent period occurred before the appearance of other seizures. Patient 13 had infantile spasms at 18 months, which responded well to steroids. Gelastic seizures then appeared as the second seizure type at age 11 years

Seven of the older patients were self-caring, of whom four were employed. One patient was in a home for adults with learning disability (patient 9, Table 1). Three of the patients were of borderline intelligence, one of low average, two of normal intelligence, and two had mild learning difficulty.

The following is an illustrative case of an adult patient whose epilepsy began in infancy but whose diagnosis was made only in adult life. After many years of treatment with antiepileptic drugs (AEDs), his epilepsy improved with stereotactic thermocoagulation of the HH.

Case 1

This patient (patient 15, Table 1) is a 30-year-old unemployed single man, who discontinued a degree in business studies because of refractory epilepsy. His epilepsy began as an infant, with episodes of smiling and laughing as he drifted off to sleep. Subsequently, more overt gelastic seizures manifested in early childhood, between ages 3 and 4 years. Puberty was normal. At age 17 years, severe tonic seizures and infrequent secondarily generalized seizures manifested. Seizures were refractory to treatment with four different AEDs [phenytoin (PHT), valproate (VPA), carbamazepine (CBZ), and phenobarbitone (PB)]. With the appearance of the more prominent tonic seizures, the gelastic seizures became less apparent, and the patient was left with residual “feelings of an urge to giggle,” which he reported as occurring in association with a brief change in the pitch of his voice. These attacks were perceived as alien, not associated with mirth, out of context, and occurred “hundreds of times a day” and caused great distress to the patient. An MRI scan (0.5 T) done in 1990 was reported to be normal. Scalp video-EEG monitoring of the seizures revealed an apparent temporal onset that was confirmed by depth electrode recordings. The depth electrodes were placed in both the frontal and temporal lobes (the HH had not been detected at this time). Consequent to the apparent confirmation of the temporal onset of his epilepsy by depth electrodes, he underwent a left temporal lobectomy in 1992. After surgery, the seizures were reduced in severity but not in frequency. He was reinvestigated in 1999 with scalp telemetry and another MRI scan (1.5 T). On this occasion, the MRI scan showed a small 0.5-cm HH, in relation to the left mamillary body. Further scalp video-EEG recordings were performed. They showed no epileptiform change on the scalp EEG during the episodes of “urge to laugh,” and the ictal EEG features of the tonic seizures were obscured by muscle artifact. The patient was reluctant to undergo further open resective surgery. Therefore, minimally invasive stereotactic thermocoagulation of the HH was planned. Depth electrodes were placed stereotactically into the HH, both cingulate gyri, both frontal cortices, and into the remaining mesial temporal structures, to establish seizure onset. With a combination of ictal recording and extraoperative stimulation, both his habitual attacks of “the urge to giggle” and the tonic seizures were shown to originate from the hamartoma. Importantly, no other site of ictal onset of the tonic seizures was demonstrated from the other cortical depth electrodes.

Stereotactic thermocoagulation of the lesion was performed under local anaesthesia, with the patient awake. After intraoperative stimulation reproduced his habitual attacks of the “urge to laugh,” the coagulating electrode was introduced to the same stereotactic coordinates from where the seizures had previously been shown to originate. The lesion was thermocoagulated with lesions created at 60, 70, and 80°C for 30 s each. The procedure was terminated in this patient when he complained of dizziness. Postoperatively, the patient did not have any neurologic or endocrine morbidity. Because this patient was well preserved with no significant preexisting neurologic morbidity or cognitive deficits, the treatment aim had been to “undertreat,” with the emphasis not only on treating the epilepsy, but also on avoiding any potential morbidity associated with the procedure. After this procedure, the attacks of the urge to laugh stopped completely, and the tonic seizures were reduced by 70%. The follow-up period was 18 months. The patient reported improvement in memory after the procedure, but this was not quantifiable on the standard neuropsychological test battery.

Another patient with HH who had atypical absences, tonic, and secondarily generalized seizures, also underwent stereotactic thermocoagulation (patient 12, Table 1). Postoperatively, no neurologic or endocrine deficits were noted. The tonic and generalized seizures improved immediately, but atypical absences improved gradually, and have been reduced by ∼70% at 1 year. He also reported an improvement in memory after the procedure and was documented to have a 3-point increase in verbal memory when tested postoperatively.

Group 2

This group consisted of three patients, all adults, in whom the epilepsy began in adult life. All of these patients were employed, and the epilepsy, although significant, was not so severe as in the first two groups. One of these patients is illustrated.

Case 2

Patient 18 is a 56-year-old woman, a teacher, who is married with three grown children, and is currently studying for a degree in art history. Menarche was normal. Her epilepsy began at age 21 years with generalized tonic–clonic seizures (GTCs). Treatment was commenced with PB and subsequently primidone (PRM; Mysoline). The second seizure type began at age 30 years. During seizures, she would fall and be out of contact, and move her hands repeatedly in a circular manner or in the sign of the cross. She would moan and mumble and appear irritable during these attacks. They would last a couple of minutes with postictal confusion.

Gelastic seizures, the third seizure type, manifested at age 30 years. During them, she continued to be aware of her surroundings, and was noted to beam or smile (but did not actually laugh out loud). This was involuntary and lasted several seconds. She reported occasions while reprimanding a student in class, in which she would suddenly start “smiling” senselessly, inappropriately, and involuntarily. These attacks were not associated with mirth. They occurred daily. MRI scan showed a 5-mm HH arising from the lateral wall of the third ventricle. The interictal EEG showed right temporal sharp waves and normal background activity. She has been taking CBZ and PRM for many years with partial response, but she continues to have two to three complex partial and gelastic seizures a week. She does not wish to consider surgical treatment.

EEG findings

Fifty scalp EEGs, six scalp video-EEG recordings, two foramen ovale telemetry recordings, two peroperative lesional, and three chronic depth electrode recordings were available for evaluation.

Background activity on scalp EEG

Eleven patients, all of whom were younger than 10 years at the time of the initial test, had serial EEGs (range, two to five). The background activity at initial assessment was slowed in all these patients. Two patients had high-voltage chaotic slow waves, and multifocal epileptiform discharges similar to hypsarrhythmia in early childhood, and one of them had infantile spasms. The initially slow background activity improved in subsequent EEGs, and normal background activity was seen in the most recent EEG in seven of the 11 patients. In two patients, the slowed background activity was seen to improve after surgical resection and control of seizures.

Nine patients, seven of whom were age 10 years or older, had a single scalp EEG. Two of these had a mild to moderate degree of slowing of background activity on the EEG. Therefore slowing of background activity on the EEG was noted less frequently in older patients.

Interictal epileptiform abnormality on scalp EEG

 Focal abnormalities. The interictal epileptiform abnormalities were multifocal in 10 patients. When multifocal, profuse epileptiform discharges occurred in the temporal (44%), frontal (50%), and midline/parasagittal (25%) regions. In nine patients, mainly focal temporal epileptiform activity was seen.

 Generalized discharges. Fifteen EEGs from six patients showed generalized slow, 1- to 3-Hz spike/polyspike-and-slow wave activity lasting 1–15 s and not accompanied by clinical change.

In patient 13 (see Table 1), repeated EEGs over a period of several years documented a change in epileptiform activity recorded, starting with infantile spasms, evolving into generalized spike–wave and multifocal discharges, during early childhood, and to a single (temporal) focus in adult life. This change occurred gradually, over a period of years, and accompanied a change in clinical seizures from more prolonged and severe complex partial seizures to milder and brief, but still complex partial seizures, and mild auras of an “urge to laugh.”

Ictal events

 Video EEG telemetry. Scalp video-EEG telemetry was performed in seven patients. Between two and four seizures were recorded in each patient, whereas one patient had innumerable brief seizures. Seizure types recorded were brief tonic seizures from sleep in three patients, gelastic seizures (in five patients), complex partial seizures (in two patients), and atypical absence (in two patients). Three patients had brief gelastic seizures that were not associated with any epileptiform change in the scalp EEG. Four patients had distinct discharges that occurred as an evolving pattern consisting of an initial abrupt diffuse attenuation of the background, followed by a brief generalized burst of fast polyspikes, and then prominent bursts of generalized rhythmic fast activity lasting a few seconds, at a frequency of between 14 and 24 Hz. These then evolved into slow spike–wave activity. These bursts lasted between 2 and 30 s. We have termed this pattern “evolving generalized fast rhythmic activity” (EGFRA; Fig. 1). The evolution of the discharge, from one type (polyspikes) to another (generalized rhythmic fast and slow spike–wave), is in keeping with an ictal pattern. The pattern was seen at ictal onset, of varying clinical semiology of tonic seizures (three patients), complex partial seizures (one patient), and atypical absences (one patient).

image

Figure 1. The evolving generalized rhythmic fast activity pattern: evolving generalized electrodecrementation followed by a burst of generalized polyspikes, which evolve into rhythmic fast activity at 14–24 Hz and ending in slow spike–wave activity with postictal attenuation.

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Direct recordings from the lesion intraoperatively with depth electrodes were performed on two patients. Spikes were seen arising from the lesion, spreading to the temporal areas in patient 5. No spikes were recorded in patient 4, who had an HH proven on pathology, as well as PP and a severe seizure disorder.

MRI findings

All hamartomas were iso- or hypointense on T1 and intermediate to high signal on T2 sequences. Lesion sizes varied between 4 and 30 mm. Eleven patients had hamartomas that were ≤1 cm (Fig. 2A). The nature of attachment of the HH was compared with the clinical manifestations of the presence of PP, the age at onset of epilepsy, and the presence of gelastic seizures.

imageimageimage

Figure 2. A: Coronal T1- and T2-weighted images of very small parahypothalamic hamartoma, arising from left mamillary body. B: Coronal T1- and T2-weighted images of large, sessile, intrahypothalamic HH. C: Coronal T1- and T2-weighted images showing a parahypothalamic, pedunculated HH (not clearly arising from either the mamillary body or the tuber cinerum).

Of the 14 patients who had intrahypothalamic hamartomas (Fig. 2B), all had moderate to severe epilepsy, including gelastic seizures, and five had PP. Thirteen (92%) had early-onset epilepsy (<10 years; mean, 2.6 years).

Five patients had parahypothalamic hamartomas (Fig. 2C). All had epilepsy, two had gelastic seizures, and three had PP. Three (60%) had late-onset epilepsy (>10 years), of whom two were of adult onset.

These results were subjected to statistical analysis with the Fisher's Exact test. The association of intrahypothalamic lesions with gelastic seizures was statistically significant (p < 0.003), as was the early onset of epilepsy in the same group (p < 0.014). The later onset of epilepsy in the parahypothalamic group, with the lesser incidence of gelastic seizures and learning difficulty was not statistically significant.

All three patients with late-onset seizures had small HHs (4–10 mm). Five of the seven patients with early-onset seizures had HHs that were >1 cm. Bigger size of the HH was associated with greater number of seizure types. Eight patients who had an HH >1 cm had between two and five seizure types (mean, 3.75). Eleven patients who had HHs that were ≤1 cm had between one and four seizure types (mean, 2.45). This difference is statistically significant (p = 0.04).

Pathology

Seven patients underwent surgical resection of their hypothalamic lesions. All showed the features of a neuronal hamartoma, the tissue consisting of grey matter with small and large neurons, diffusely distributed or clustered in the neuropil with glial nuclei interspersed (Fig. 3A), resembling normal hypothalamus. In some, parts of the lesion simply resembled normal grey matter or were relatively hypocellular. In four cases, occasional very large multipolar neurons with coarse dendritic processes were present. Streams of myelinated nerve fibers and haphazardly arranged individual myelinated and unmyelinated nerve fibers ran through the grey matter in most of the lesions (Fig. 3B). In addition, in five lesions (from patients 3, 4, 5, 7, and 11), small aggregates of cells were found with round hyperchromatic nuclei with dense chromatin or slightly open nuclear chromatin, and a small nucleolus, and this feature was particularly prominent in one hamartoma (patient 7; Fig. 3C).

imageimageimage

Figure 3. A: Grey matter with small and large neurons, indistinguishable from normal hypothalamic tissue. Hematoxylin and eosin. Scale bar = 100 μm. B: Bundles of axons against a background of haphazardly arranged nerve fibers. Glees and Marsland silver impregnation method. Scale bar = 400 μm. C: An aggregate of small round cells, some with dense nuclei and others with open nuclear chromatin and nucleoli. Hematoxylin and eosin. Scale bar = 100 μm.

Immunocytochemistry for glial fibrillary acidic protein showed fibrillary astrocytosis in four cases. No nuclear atypia appeared in either the neuronal or glial component, and no mitotic figures were seen in any of the cases to suggest the possibility of a neoplasm. Fibrovascular connective tissue with large vessels was found in intimate relation with the grey matter in three cases, and numerous corpora amylacea were seen scattered in the neuropil in one.

Anterior temporal lobe resection specimens from two patients showed only mild subpial gliosis and white matter astrocytosis. No cell loss was found in the hippocampus or the amygdala.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

The clinical spectrum of these patients demonstrates first, adult onset of epilepsy in HH, and second, evolution of severe epilepsy in childhood to a milder form in later life in some patients.

Epilepsy in adults with HH

Not just a disease of childhood

Adult onset of epilepsy with HH has only recently been reported (9,14). All three patients with adult-onset epilepsy in our cohort are high functioning, of at least average intelligence, and in full-time employment. In Striano's study (14), patient 3 developed epilepsy at the age of 20 and was of normal intelligence. Therefore they are quite different from the commonly understood presentation of patients with HH who have severe epilepsy that starts in childhood and is associated with catastrophic behavioral and cognitive difficulties (12,15).

The epilepsy is milder

The three patients with adult onset had milder partial epilepsy. The number of seizure types were one to two, with infrequent generalized seizures. In contrast, the children in our series with early-onset epilepsy had between two and five seizure types. Further, these adults did not progress to develop the more severe symptomatic generalized epilepsy, as children with early-onset epilepsies were likely to (five of eight children in our series).

Gelastic seizures are less prominent

Gelastic seizures occurred only in patient 18 of the three adult-onset patients, but in all of the HH patients with early-onset epilepsy whose onset was at younger than 5 years. It appears that gelastic seizures are not as prominent a feature of epilepsy in adult patients with HHs as they are in children. Our results suggest that this may be related to the size and location of the HH. Patients with intrahypothalamic HHs were more likely to present early (13 of 14 patients with intrahypothalamic HH in our series) and have gelastic seizures (14 of 14 patients).

The patterns of evolution of epilepsy in HH

An evolution of the epilepsy occurs from onset in childhood to adult life. First, gelastic seizures occurred at onset in all our patients with early-onset epilepsy, but they did not always persist into later life. Four of our eight adult patients whose epilepsy began in early childhood no longer had gelastic seizures in adult life, and the gelastic seizures died down in their teens. In two of these patients, the gelastic seizures subsided completely, whereas in the other two, only gelastic auras remained, which the patients did not recognize as seizures, but as an incomprehensible “urge to laugh,” which they did not associate with the epilepsy. This has been reported before (8). This change in the gelastic nature of seizures in adult life contributes to delayed diagnosis because this is an important clinical clue to the presence of the HH. Other seizure types appear in later childhood or teens. No clear relation is seen between the time of the disappearance of gelastic seizures and the appearance of other seizure types.

Second, the multiple seizure types and complex epilepsy, which begins in childhood, sometimes evolve into one or two distinct seizure types. This is commonly complex partial seizures, tonic seizures, or atypical absence seizures.

Third, complex partial seizures of temporal lobe semiology occurred in four of our patients, and these were clinically interpreted, in the absence of imaging data showing the HH, as temporal lobe epilepsy (TLE). This misinterpretation resulted in two of these patients undergoing temporal lobectomy in the early 1990s, before the detection of the HHs. This was after confirmation of the apparent temporal ictal onset with intracranial electrode recording. It has been previously recognized that HH maybe associated with seizures that can be erroneously localized to the temporal or frontal lobes (16), and that is highlighted again.

Fourth, tonic seizures, with nocturnal exacerbation, also are noted, and presumably these seizures are responsible for some of the “drop attacks.” We suggest therefore that HH needs to be considered in the differential diagnosis of complex partial and tonic seizures, especially when there is a gelastic component, which must be particularly questioned for in history taking. Patients may not volunteer information about this, not recognizing its relevance to their epilepsy.

Finally, when the epilepsy evolves into symptomatic generalized epilepsy, atypical absences are frequent and common, and probably contribute to cognitive decline, especially in children (17). The factors that cause the development of symptomatic generalized epilepsy in some patients and partial epilepsy in others are still not clear.

Hypothalamic hamartoma can be seen with infantile spasms

Although it is well known that focal lesions cause hypsarrhythmia (18), its association with HHs is not well recognized. In one of our patients, hypsarrhythmia developed with clinical infantile spasms, which began later than usual, at age 18 months, and another had the EEG features of hypsarrhythmia, but no clinical spasms. The first patient responded to steroid treatment and recovered, had mild epilepsy in later life, normal mainstream education, and is now in full-time employment. The other patient (who also had PP) had learning difficulty and severe symptomatic generalized epilepsy. Infantile spasms as the presenting seizure type in one patient also was presented in a recent report (19).

Stereotactic thermocoagulation

Stereotactic procedures have been recently described for the treatment of HH (4,20). Open invasive surgical procedures in the region of the hypothalamus are difficult and have considerable risks of morbidity; hence alternative procedures merit evaluation. Stereotactic procedures of the hypothalamus were being performed in the 1960s for what was considered deviant sexuality, such as pedophilia (21). Once the hamartoma has been demonstrated to be the source of the seizures by prolonged EEG recording and stimulation with intracranial electrodes, it is possible to proceed to lesioning. Two of our patients had this performed under local anaesthesia, and they were able to tell us of any adverse symptoms experienced during the procedure; neither had any significant side effects. One patient had dramatic improvement in his seizures, which were reduced by >70%. He was satisfied with this result, because he was unwilling to consider open surgery. The other patient not only had a significant improvement in his seizures, but also reported an improvement in memory after the procedure. This was quantifiable on neuropsychological testing as a gain of 3 points on verbal memory. His epilepsy was mainly symptomatic generalized with frequent atypical absences, tonic, and GTC attacks. Interestingly, the tonic seizures improved immediately, but the atypical absences were reduced gradually, over a period of a year. Emerging experience suggests that patients with HH and entrenched symptomatic generalized epilepsy may not have as good a resolution of epilepsy as do patients who have symptomatic partial epilepsy, despite treatment directed at the hamartoma (12,19). This may be a consequence of the symptomatic generalized epilepsy being established rather than of the stereotactic procedure being inadequate. More experience with this procedure and longer follow-up are needed to clarify this issue.

The particular advantages of this procedure are, first, the potential positive neuropsychological outcome in comparison with the open surgical option. Resective surgery has been documented to render some patients seizure free, but the posttreatment neuropsychological status has never been systematically documented. We find that stereotactic thermocoagulation is particularly suitable for cooperative patients who are cognitively preserved. Second, stereotactic thermocoagulation is less invasive and quicker, and most important, causes less tissue destruction than does open resective surgery. The gamma knife treatment also is noninvasive, but the effect is delayed. The mean time for seizure reduction with gamma knife treatment was 9 months [range, 3–36 months (6)], whereas the results are immediate with stereotactic thermocoagulation.

Electroclinical issues in HH

Berkovic et al. (1) reported four patients with HH. Three of their patients, each of whom had at least five seizures, showed an ictal pattern of “generalized onset with low voltage rhythmic fast activity and/or generalized suppression of background rhythms, sometimes preceded by single or multiple generalized spike–wave complexes.” Interictal abnormalities were generalized slow spike–wave activity, infrequent focal spikes, and diffusely slowed background activity. Others (2,13) also reported similar findings. These features closely resemble the pattern we have reported, although we noted that slow spike–wave activity generally followed the rhythmic fast activity.

We observed a variable degree of slow background activity in all the initial EEG recordings. This may be a result of modulation by the HH of thalamocortical oscillations responsible for normal background rhythms. It also is possible that some of the background slowing may be a nonspecific effect of frequent epileptiform activity. Curiously, consecutive recordings show that this slowing of background activity seems to mature and improve with time, and records obtained in later life no longer show the same degree of slowing, despite the presence of abundant concurrent epileptiform discharges.

The hamartoma activates profuse focal epileptiform discharges that are recorded over the cortex by the scalp EEG. In our study, focal epileptiform discharges clustered around the temporal, the midline, and the frontal regions. It has been documented from studies in the rat brain that the hypothalamus has preferential connections to the hippocampal, the mesial frontal, and the limbic cortex (22,23). It is possible, therefore, that the hamartoma initiates epileptiform discharge, which is then preferentially propagated to these parts of the cerebral cortex (via the hypothalamus). The other possibility that independent epileptogenesis occurs in the cortex also must be considered. Some evidence suggests this. First, Kahane et al. (7) reported three patients with HH who underwent depth electrode studies in whom it was demonstrated that gelastic seizures originated from the hamartoma, but tonic seizures originated independently from the cortex. Second, Sisodiya et al. (24) reported changes in volumetric analysis of MRI in two patients with HH, not seen in normal individuals. However, it was repeatedly shown that surgery and other treatments that treat the hamartoma can result in reduction of all seizure types (and not only gelastic seizures), suggesting that the hamartoma is fundamentally involved in generating all seizure types (5,12). Pathological examination of excised cerebral cortex that was apparently the ictal-onset zone has not shown any pathologic abnormality. Further, excision of the apparently involved cortex has not resulted in improvement of seizures (15,25). The most plausible explanation is that the hamartoma, being intrinsically epileptogenic, facilitates secondary epileptogenesis in the cortex, and the clinical manifestation of the seizure is dependant on the region of cortex so activated.

Finally, the point must be made that the EGFRA pattern described earlier is not specific to HH. It has been observed in other cases of symptomatic generalized epilepsy, often of uncertain etiology. We have seen this pattern in a patient with a small mesial frontal dysembryoplastic neuroepithelial tumor (DNET), again, like the HH, a lesion close to the midline. Therefore, although the EGFRA pattern is striking when it occurs, it is not specific and has a low sensitivity (four of 19 cases).

The pathologic and pathophysiologic relation between the brain and the hypothalamic hamartoma

Pathologically, all the cases examined consisted of lesions containing mature neurons and unmyelinated and myelinated axons, the latter often organized in bundles, suggesting connectivity. Connection with the brain is necessary for the functional abnormalities associated with HHs (26), and the endocrine capacity of the neurons has been confirmed in at least one case by immunolabeling with gonadotrophin-releasing hormone antiserum (27). The presence of the aggregates of small round cells has not been previously emphasized in descriptions of neuronal HHs. They probably represent rests of germ cells and immature neurons within the hamartoma and resemble the microdysgenetic nodules sometimes seen in temporal lobe resections for chronic epilepsy, are frequently associated with DNETs (28), and probably represent rests of germ cells and immature neurons within the hamartoma. The hypothalamic hamartoblastoma, seen in neonates with the lethal Pallister–Hall syndrome, is composed almost entirely of such cells (29). The undifferentiated cells, although relatively well ordered and lacking in mitotic activity, were thought to be neoplastic. Nurbhai et al. (30) contest the neoplastic nature of these lesions, stating that the presence of such cells in a hamartoma is not unexpected in infancy. Although four of our patients with such cells in their lesions were very young, one was an adult, and none had the other stigmata of the Pallister–Hall syndrome.

In summary, the spectrum of epilepsy associated with HH ranges from the severe with multiple seizure types when the onset is early to a milder form when the onset is later in life. Cognitive and behavior difficulties are less with later onset. Gelastic seizures are a prominent feature of early-onset epilepsy but are reduced to “auras” of wanting to laugh, or totally disappear in some patients as they get older. Complex partial (pseudotemporal), tonic, atypical absences, and gelastic are the common seizure types noted in adults with HH. For cognitively preserved patients, minimally invasive procedures such as stereotactic thermocoagulation may be a superior treatment modality, and we have presented two patients in whom the treatment has been safe and effective.

Acknowledgments

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgment:  We thank Professor S. F. Berkovic and Dr. L. Parmaggiani for kindly reviewing the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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